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Molecular Characterization of Enzalutamide-treated Bone Metastatic Castration-resistant Prostate Cancer
Abstract
Background:
Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).
Objective:
To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.
Design, setting, and participants:
In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.
Outcome measurements and statistical analysis:
Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.
Results and limitations:
Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ≥ 50% and ≥ 90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (> 75%) and CYP17 (> 10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.
Conclusions:
The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.
Patient summary:
We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.
Trial registration:
ClinicalTrials.gov identifier NCT01091103.
... Efstathiou et al [25,26] reported on the relationships between changes in blood and bone-marrow androgen levels after treatment with ENZ or abiraterone, as well as the therapeutic effects. T concentrations declined to less than picogram-per-milliliter levels, and remained at that level, during treatment with abiraterone [25]. ...
... T concentrations declined to less than picogram-per-milliliter levels, and remained at that level, during treatment with abiraterone [25]. In contrast to the inhibition of androgen biosynthesis by abiraterone, T levels in blood and bone marrow increased, accompanied by a nuclear-to-cytoplasmic AR shift, following 8 wk of ENZ therapy [26]. T levels increased after 8 wk of treatment in most patients for whom paired samples of both blood (40/51, 78%) and bone marrow aspirate (34/44, 77%) were available [26]. ...
... In contrast to the inhibition of androgen biosynthesis by abiraterone, T levels in blood and bone marrow increased, accompanied by a nuclear-to-cytoplasmic AR shift, following 8 wk of ENZ therapy [26]. T levels increased after 8 wk of treatment in most patients for whom paired samples of both blood (40/51, 78%) and bone marrow aspirate (34/44, 77%) were available [26]. Similarly, in the present study, T, DHT, DHEA-S, and A-dione levels tended to increase after ENZ administration, and T, DHT, and A-dione levels were significantly higher by 12 and 24 wk after treatment initiation. ...
Background
Enzalutamide (ENZ) is used to treat patients with castration-resistant prostate cancer (CRPC). However, the kinetics of serum androgens before and after ENZ treatment are unknown.
Objective
To elucidate the kinetics of serum androgens and explore the possibility of identifying a useful marker for predicting the effects of ENZ.
Design, setting, and participants
We conducted a prospective study from 2014 to 2018 at Gunma University Hospital and related facilities. Data were analyzed for 104 patients with CRPC treated with ENZ.
Outcome measurements and statistical analysis
We measured serum androgen levels using liquid chromatography-tandem mass spectrometry. Relationships with outcomes were assessed using multivariable Cox regression and log-rank analyses.
Results and limitations
The median age of the patients was 73 yr. Median serum testosterone, dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone sulfate levels were 49.0, 5.8, 222.2, and 326.3 pg/ml, respectively. We performed multivariate analysis using Cox regression to predict prostate-specific antigen progression–free survival (PSA-PFS) and overall survival (OS). Hemoglobin level (≥12.5 vs <12.5 g/dl), docetaxel treatment history (no vs yes), and DHT level (≥5.9 vs <5.9 pg/ml) were significant predictors of PSA-PFS (p < 0.05). Eastern Cooperative Oncology Group performance status (0 vs. 1–2), hemoglobin level (≥12.5 vs <12.5 g/dl), presence of visceral metastasis (no vs yes), amount of bone metastasis (extent of disease 0–2 vs 3–4), and docetaxel treatment history (no vs yes) were significant predictors of OS (p < 0.05). Binomial logistic analysis of the predictors of any grade of anorexia, malaise, and fatigue showed that the presence of visceral metastasis and a low DHT level (<5.9 pg/ml) were significant.
Conclusions
Our results suggest that serum androgen levels before ENZ treatment may be useful for predicting efficacy, prognosis, and the incidence of adverse events.
Patient summary
We measured blood levels of testosterone and other male hormones before treatment with enzalutamide among men with prostate cancer resistant to castration. We found that the levels of these hormones may be useful for predicting the efficacy of enzalutamide treatment, prognosis, and the occurrence of adverse side effects.
... AR-V7 [19,57,59] Abbreviations: PBMC-Peripheral blood mononuclear cell. Table 2. AR-Vs as prognostic and predictive markers in CRPC based on clinical studies. ...
... [58] High AR-V7 and AR-V7/ AR-FL ratio in nuclear of PCa tissues are associated with shorter BCR-free survival. [57] AR-V7 in bone marrow is associated with resistance to ENZ. [59] CTC AR-V7 is associated with shorter PFS and OS on BAT and enzalutamide, but not predictive of treatment effects. [60,61] Nivolumab plus ipilimumab showed modest efficacy in CTC AR-V7(+) patients irrespective of enzalutamide addition. ...
... Chen et al.'s immunohistochemistry-based study demonstrated that high nuclear AR-V7 expression and high nuclear AR-V7/AR-FL ratio were associated with shorter biochemical recurrence-free survival in a relatively large patient cohort [57]. Moreover, the absence of AR-V7 in bone marrow biopsies from mCRPC was associated with better treatment response to enzalutamide in a different study [59]. While most pathological studies mainly focus on AR-V7 because of the limited availability of variantspecific antibodies other than AR-V7, Kohli et al. reported that AR-V9 mRNA is often coexpressed with AR-V7 in mCRPC tissues [50]. ...
Simple Summary
Androgen receptor splice variants (AR-Vs) play an important role in prostate cancer progression, especially as a putative resistance mechanism against AR-targeted therapies. Recent technological advances have enabled detection of AR-Vs in many types of human specimens including circulating tumor cells. Here, we discuss the biology of AR-Vs, the clinical utility of AR-Vs as prognostic and predictive biomarkers, and AR-Vs as potential therapeutic targets with a special focus on AR-V7.
Abstract
Over the past decade, advances in prostate cancer research have led to discovery and development of novel biomarkers and effective treatments. As treatment options diversify, it is critical to further develop and use optimal biomarkers for the purpose of maximizing treatment benefit and minimizing unwanted adverse effects. Because most treatments for prostate cancer target androgen receptor (AR) signaling, aberrations affecting this drug target are likely to emerge following the development of castration-resistant prostate cancer (CRPC), and it is conceivable that such aberrations may play a role in drug resistance. Among the many AR aberrations, we and others have been studying androgen receptor splice variants (AR-Vs), especially AR-V7, and have conducted preclinical and clinical studies to develop and validate the clinical utility of AR-V7 as a prognostic and potential predictive biomarker. In this review, we first describe mechanisms of AR-V generation, regulation and their functions from a molecular perspective. We then discuss AR-Vs from a clinical perspective, focusing on the significance of AR-Vs detected in different types of human specimens and AR-Vs as potential therapeutic targets.
... Through various AR-related mechanisms, prostate cancer eventually escapes ADT and progresses toward castration resistance [50][51][52][53][54][55][56][57][58][59][60][61][62][63][64]. Among these adaptive strategies are AR overexpression and gene amplification. ...
... AR splice variants (ARVs) are also involved in the hormonal resistance of PC [64]. ARV7, the most abundantly expressed ARV in human cell lines and clinical samples, has been found to be significantly higher in patients who do not respond to ENZ [63]. Its expression has been associated with lower PSA response rates and a shorter median OS in patients treated with ADT and NHAs [65]. ...
Androgen deprivation therapy (ADT) remains the cornerstone of advanced prostate cancer treatment. However, the progression towards castration-resistant prostate cancer is inevitable, as the cancer cells reactivate androgen receptor signaling and adapt to the castrate state through autoregulation of the androgen receptor. Additionally, the upfront use of novel hormonal agents such as enzalutamide and abiraterone acetate may result in long-term toxicities and may trigger the selection of AR-independent cells through “Darwinian” treatment-induced pressure. Therefore, it is crucial to develop new strategies to overcome these challenges. Bipolar androgen therapy (BAT) is one such approach that has been devised based on studies demonstrating the paradoxical inhibitory effects of supraphysiologic testosterone on prostate cancer growth, achieved through a variety of mechanisms acting in concert. BAT involves rapidly alternating testosterone levels between supraphysiological and near-castrate levels over a period of a month, achieved through monthly intramuscular injections of testosterone plus concurrent ADT. BAT is effective and well-tolerated, improving quality of life and potentially re-sensitizing patients to previous hormonal therapies after progression. By exploring the mechanisms and clinical evidence for BAT, this review seeks to shed light on its potential as a promising new approach to prostate cancer treatment.
... Of the twenty-seven SNPs assessed in the enzyme target and metabolism pathway, five SNPs in two genes, CYP3A4 (rs2242480; rs4646437; rs4986910), and CYP3A5 (rs15524; rs776746) were significantly associated with modifying finasteride concentrations. These results suggest that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway Molecular characterization of enzalutamidetreated bone metastatic castrationresistant prostate cancer [10] Prospective phase 2 study 60 patients Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. ...
... Chau et al. [9] found that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway. Efstathiou et al. [10] reported that AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. The presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). ...
The most prevalent solid tumor in men worldwide is prostate cancer. The need for biomarkers to guide management choices is critical given the frequency of prostate cancer and its relatively lengthy clinical course. Based on a patient's unique risk stratification, which considers pathologic characteristics from a prostate biopsy, prostate-specific antigen (PSA) level, imaging, and other patient factors, decisions about localized prostate cancer treatment options, such as active surveillance, surgical excision, or targeted radiation, are made. An attractive method for thorough cancer analysis is to use "liquid biopsies" made up of analytes from a peripheral blood draw. These methods can be used as prognostic and predictive biomarkers as well as ready tissue sources for molecular profiling during the course of a disease and are straightforward, safe, and simple to repeat. Researchers conduct an examination of articles that are in accordance with the issue to be studied. Articles used in literature review are obtained through the database of international journal providers through PubMed, we investigated eleven clinical studies and discussed what happened in these clinical studies and the extent of the effectiveness of liquid biopsy in prostatic cancer, in one study there was relative impact of common circulating tumor DNA alterations on patient response to the most widely used large, randomize advanced prostate cancer. Other studies reported that ZNF660 methylation analysis can potentially help to stratify low-/intermediate-grade PCs into indolent vs. more aggressive subtypes. Another study found that tumor-derived biomarkers in platelets of CRPC patients enabled prediction of the outcome after abiraterone therapy with higher accuracy than baseline serum PSA or PSA response. One study reported that de novo positive CTC count after androgen deprivation therapy is probably due to a passive mechanism associated with the destruction of the tumor. In this review, we suggest that liquid biopsy could be used as biomarker for prostatic cancer, Further studies are needed to enhance liquid biopsy efficacy.
... The AR signaling can drive the onset of CRPC under the conditions of persistent ADT treatment. The AR-Vs are thus commonly expressed in the CRPC tumors as an alternative to AR-FL signaling, potentially functioning in a manner distinct from other AR isoforms [83][84][85][86][87][88]. The AR-V7, for example, has been identified as the most clinically relevant AR-V owing to the fact that it lacks an LBD, yet is capable of maintaining combinatorial activity under low androgen conditions. ...
... The AR-V7, for example, has been identified as the most clinically relevant AR-V owing to the fact that it lacks an LBD, yet is capable of maintaining combinatorial activity under low androgen conditions. High expression levels for this variant have been observed in 75% of the patients with CRPC, despite being present in <1% of primary PCA cases [83][84][85]88,89]. The AR-V7, AR-V3, and AR-V9 have also recently been detected at high expression levels within the PCA cells following treatment with abiraterone, maintaining the AR signaling activity in an androgen-independent manner conducive to the CRPC growth [76,[90][91][92][93]. ...
Despite aggressive treatment and androgen-deprivation therapy, most prostate cancer patients ultimately develop castration-resistant prostate cancer (CRPC), which is associated with high mortality rates. However, the mechanisms governing the development of CRPC are poorly understood, and androgen receptor (AR) signaling has been shown to be important in CRPC through AR gene mutations, gene overexpression, co-regulatory factors, AR shear variants, and androgen resynthesis. A growing number of non-AR pathways have also been shown to influence the CRPC progression, including the Wnt and Hh pathways. Moreover, non-coding RNAs have been identified as important regulators of the CRPC pathogenesis. The present review provides an overview of the relevant literature pertaining to the mechanisms governing the molecular acquisition of castration resistance in prostate cancer, providing a foundation for future, targeted therapeutic efforts.
... These mechanisms include 1) overexpression of AR (Chen et al., 2004;Koivisto et al., 1997;Linja et al., 2001), causing sensitization of cancer cells to low levels of androgens (Waltering et al., 2009), 2) somatic point mutations in the AR that reduce the steroid specificity of the receptor (Bohl et al., 2005;Korpal et al., 2013;Sun et al., 2006), 3) alternative AR gene splicing, including the expression of ligand-independent, constitutively active, AR splice variants (Antonarakis et al., 2017;Sun et al., 2010;Watson et al., 2010), and 4) induction of Studies focused on mechanisms of acquired Enza resistance have suggested that the resistance mechanisms are similar to those involved in the development of CRPC. Mechanisms suggested to be involved include, e.g., mutations (Joseph et al., 2013;Korpal et al., 2013) and splice variants of the AR (Antonarakis et al., 2017;Li et al., 2013;Scher et al., 2016), signaling pathways that bypass androgen signaling (Arora et al., 2013;Isikbay et al., 2014), increased intratumoral androgen biosynthesis (Efstathiou et al., 2015;Liu et al., 2015), a switch from adenocarcinoma to neuroendocrine PCa (Beltran et al., 2016;Ku et al., 2017;Mu et al., 2017) and the contributions of the factors in the tumor microenvironment such as inflammatory cytokines (Handle et al., 2016); there are also data showing that glucocorticoid receptor (GR) could recapitulate, at least partially, the AR action in CRPC settings (Prekovic et al., 2018). However, proof for the mechanisms is still largely lacking. ...
... Our results are in agreement with those observed in earlier studies showing elevated A-dione and T levels in the bone marrow aspirates of patients with bone metastases treated with Enza (Efstathiou et al., 2015), with the exception that in our model, DHT was the main active androgen in the resistant tumors. It has been shown that although castration reduces circulating T levels by 90-95% (Labrie et al., 1980(Labrie et al., , 1985Moghissi et al., 1984), intraprostatic DHT is typically reduced by only 50% after medical or surgical castration, and there is no decrease in A-dione concentrations in the prostate after castration (Bé langer et al., 1989;Miyamoto et al., 1998). ...
Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Uusing xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance, and an indication of the need for further androgen blockage. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.
... [6][7][8] The intratumoral androgen concentration is high, and increasing prostate-specific antigens (PSAs) remains an important clinical indicator for disease progression once abiraterone or enzalutamide resistance arises. 9,10 However, previous studies have shown that abiraterone achieved limited clinical efficacy in patients with enzalutamide resistance and vice versa. [11][12][13] Such findings indicate that the mechanisms underlying resistance may be common to both these next-generation AR pathway inhibitors (ARPIs). ...
... 10 These results all support the importance of the androgen-AR axis after abiraterone or enzalutamide resistance. 9,50 Notably, long-term treatment of enzalutamide resulted in an increase of 3bHSD1 activity in VCaP cells, which also express ARv7, indicating the co-existence of multiple resistant mechanisms. ...
Novel strategies for prostate cancer therapy are required to overcome resistance to abiraterone and enzalutamide. Here, we show that increasing 3βHSD1 after abiraterone and enzalutamide treatment is essential for drug resistance, and biochanin A (BCA), as an inhibitor of 3βHSD1, overcomes drug resistance. 3βHSD1 activity increases in cell lines, biopsy samples, and patients after long-term treatment with enzalutamide or abiraterone. Enhanced steroidogenesis, mediated by 3βHSD1, is sufficient to impair enzalutamide function. In patients, accelerated abiraterone metabolism results in a decline of plasma abiraterone as disease progresses. BCA inhibits 3βHSD1 and suppresses prostate cancer development alone or together with abiraterone and enzalutamide. Daidzein, a BCA analog of dietary origin, is associated with higher plasma abiraterone concentrations and prevented prostate-specific antigen (PSA) increases in abiraterone-resistant patients. Overall, our results show that 3βHSD1 is a promising target to overcome drug resistance, and BCA suppresses disease progression as a 3βHSD1 inhibitor even after abiraterone and enzalutamide resistance.
... Enzalutamide, a second-generation small-molecule inhibitor of the androgen receptor (AR), has been approved for patients with metastatic castration-resistant prostate cancer (PCa) (mCRPC) after androgen deprivation therapy failure [1][2][3]. However, resistance develops within six months in patients with initial responses [4][5][6][7][8][9]. In addition, the bone is the most frequent site for PCa metastases, as nearly 90% of patients die from bone metastases [10]. ...
... Although various mechanisms of enzalutamide resistance have been identified [4,5,8,9,11], targeting only cancer cells is unlikely to achieve the goal of overcoming drug resistance due to the heterogeneity and plasticity/evolution of the cancer cell population. In contrast, the microenvironment influences not only cancer initiation, progression, and metastases, but also treatment responses [12][13][14][15][16][17][18][19][20][21][22][23][24]. ...
Enzalutamide resistance has been observed in approximately 50% of patients with prostate cancer (PCa) bone metastases. Therefore, there is an urgent need to investigate the mechanisms and develop strategies to overcome resistance. We observed enzalutamide resistance in bone lesion development induced by PCa cells in mouse models. We found that the bone microenvironment was indispensable for enzalutamide resistance because enzalutamide significantly inhibited the growth of subcutaneous C4–2B tumors and the proliferation of C4–2B cells isolated from the bone lesions, and the resistance was recapitulated only when C4–2B cells were co-cultured with osteoblasts. In revealing how osteoblasts contribute to enzalutamide resistance, we found that enzalutamide decreased TGFBR2 protein expression in osteoblasts, which was supported by clinical data. This decrease was possibly through PTH1R-mediated endocytosis. We showed that PTH1R blockade rescued enzalutamide-mediated decrease in TGFBR2 levels and enzalutamide responses in C4–2B cells that were co-cultured with osteoblasts. This is the first study to reveal the contribution of the bone microenvironment to enzalutamide resistance and identify PTH1R as a feasible target to overcome the resistance in PCa bone metastases.
... First, the association of high T after Abi with worse outcomes to Enza may be partially explained by incomplete testosterone suppression while on Abi, or testosterone "bounce" following Abi revealed in a recent study [6]. Second, Abi can be metabolized to delta-4-abiraterone (D4A) [7], which has similar anti-androgen properties to Enza, and Enza is known to induce adaptive T upregulation [8,9]. Therefore, the lack of response to Enza in men with high post-Abi T could be potentially explained by the pharmacokinetic properties of Abi. ...
Bipolar androgen therapy (BAT) is effective in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients. Treatment selection biomarkers are needed due to other therapies that can be equally efficacious. We performed post-hoc analysis to determine whether baseline serum testosterone (T) is a treatment selection marker in the TRANSFORMER study, a randomized trial of abiraterone-pretreated mCRPC patients assigned to BAT (n = 94) or enzalutamide (n = 101). The findings suggest that patients with poor outcomes to abiraterone and serum T ≥ 20 ng/dL may benefit preferentially from BAT over enzalutamide. Baseline testosterone could be considered in the treatment selection process when BAT is an option.
... [46][47][48][49] This Androgen deprivation therapy is a gold standard treatment. Leuprorelin and goserelin are two examples (GnRHR) [50][51][52][53]: & that lowers blood hormone levels or androgen transporter antagonists, which prevent the entry of testosterone within the cells (cancer tumours), respectively. Competitive AR antagonists' prevention of androgen's ability to bind to androgen receptors Enzalutamide (Second generation AR antagonists). ...
... Second-generation novel hormonal therapy (NHT), including abiraterone and enzalutamide, has been approved by the Food and Drug Administration (FDA) for the treatment of CRPC and demonstrates good clinical tolerance and overall survival improvement for CRPC patients [4,5]. However, resistance to abiraterone or enzalutamide remains a painful problem for biologists and clinicians [7,8]. ...
Background:
Prostate cancer threatens the health of men over sixty years old, and its incidence ranks first among all urinary tumors among men. Enzalutamide remains the first-line drug for castration-resistant prostate cancer, however, tumors inevitably become resistant to enzalutamide. Hence, it is of great importance to investigate the mechanisms that induce enzalutamide resistance in prostate cancer cells.
Methods:
Bioinformatic analyzing approaches were used to identified the over-expressed genes in prostate cancer tumor tissues from three GEO datasets. qRT-PCR, western blotting and immunochemistry/In situ hybridization staining assays were performed to assess the expression of SNHG4, RRM2, TK1, AURKA, EZH2 and RREB1. Cell cycle was measured by flow cytometry. CCK-8, plate colony formation and EdU assays were performed to assess the cell proliferation. Senescence-associated β-Gal assay was used to detect the cell senescence level. γ-H2AX staining assay was performed to assess the DNA damages of PCa cells. Luciferase reporter assay and RNA immunoprecipitation assay were performed to verify the RNA-RNA interactions. Chromatin immunoprecipitation assay was performed to assess the bindings between protein and genomic DNA.
Results:
We found that RRM2 and NUSAP1 are highly expressed in PCa tumors and significantly correlated with poor clinical outcomes in PCa patients. Bioinformatic analysis as well as experimental validation suggested that SNHG4 regulates RRM2 expression via a let-7 miRNA-mediated ceRNA network. In addition, SNHG4 or RRM2 knockdown significantly induced cell cycle arrest and cell senescence, and inhibited DNA damage repair and cell proliferation, and the effects can be partially reversed by let-7a knockdown or RRM2 reoverexpression. In vitro and in vivo experiments showed that SNHG4 overexpression markedly enhanced cell resistance to enzalutamide. RREB1 was demonstrated to transcriptionally regulate SNHG4, and RREB1 was also validated to be a target of let-7a and thereby regulated by the SNHG4/let-7a feedback loop.
Conclusion:
Our study uncovered a novel molecular mechanism of lncRNA SNHG4 in driving prostate cancer progression and enzalutamide resistance, revealing the critical roles and therapeutic potential of RREB1, SNHG4, RRM2 and let-7 miRNAs in anticancer therapy.
... Secondly, enzalutamide may be less susceptible to adverse cardiac events because of increased testosterone level. [21] As enzalutamide inhibits androgen receptors, it may disrupt the negative feedback, which eventually results in increased testosterone. [22] An elevated testosterone level may increase nitric oxide production and promote coronary artery relaxation. ...
Background
While the cardiovascular risks of androgen receptor pathway inhibitors have been studied, they were seldom compared directly. This study compares the risks of major adverse cardiovascular events (MACE) between enzalutamide and abiraterone among prostate cancer (PCa) patients.
Methods
Adult PCa patients receiving either enzalutamide or abiraterone in addition to androgen deprivation therapy in Hong Kong between 1 December 1999 and 31 March 2021 were identified in this prospective cohort study. Patients who switched between enzalutamide and abiraterone, initiated abiraterone use without steroids, or experienced prior cardiac events were excluded. Patients were followed-up until 31 September 2021. The primary outcome was MACE, a composite of stroke, myocardial infarction (MI), Heart failure (HF), or all-cause mortality. The secondary outcomes were individual components of MACE. Inverse probability treatment weighting was used to balance covariates between treatment groups.
Results
In total, 1015 patients were analyzed (559 enzalutamide users and 456 abiraterone users; mean age 70.6 ± 8.8 years old) over a median follow-up duration of 11.3 (IQR: 5.3–21.3) months. Enzalutamide users had significantly lower risks of 4P-MACE (weighted hazard ratio (wHR) 0.71 [95% confidence interval (CI) 0.59–0.86], p < 0.001), which remained consistent in multivariable analysis (p < 0.001). Such an association may be stronger in patients aged ≥ 65 years or without diabetes mellitus and was independent of bilateral orchidectomy. Enzalutamide users also had significantly lower risks of MI (wHR 0.57 [95% CI 0.33–0.97], p = 0.040) and all-cause mortality (wHR 0.71 [95% CI 0.59–0.85], p < 0.001).
Conclusion
Enzalutamide was associated with lower cardiovascular risks than abiraterone in PCa patients.
... Moreover, bone biopsies often yield suboptimal samples for genomic evaluation, as they often produce an inadequate amount of viable tumor cells, and the unique tissue processing procedures may further decrease the analyzable amount of DNA [23,24]. Other studies have reported biopsy failure rates higher than other cancer types, including a 31% failure rate in the biomarker-selected phase 3 trial PROfound [9,25,26]. ...
Simple Summary
The detection of specific genomic alterations is growing in importance for therapeutic decision-making in advanced prostate cancer. Traditional methods using tumor tissue samples can be challenging for prostate cancer, as the disease is often characterized by an extended disease history and a propensity for metastasis to the bone. Given the circumstances, liquid biopsy can be an attractive alternative. In this study, we evaluated the clinical usefulness of a liquid biopsy using blood samples instead of tumor tissues. The results showed that the liquid biopsy was able to evaluate cancer-related genomic changes in most patients, and it successfully detected clinically important mutations, exhibiting the high sensitivity of liquid biopsy compared to the tissue sequencing results. The liquid biopsy also enabled a genomic evaluation in cases where it would have been not possible using only archived tumor tissue samples. This study suggests that a liquid biopsy can be a good option for checking gene changes in advanced prostate cancer patients.
Abstract
Traditional tissue-based assessments of genomic alterations in castration-resistant prostate cancer (CRPC) can be challenging. To evaluate the real-world clinical utility of liquid biopsies for the evaluation of genomic alterations in CRPC, we preemptively collected available plasma samples and archival tissue samples from patients that were being treated for clinically confirmed CRPC. The cell-free DNA (cfDNA) and tumor tissue DNA were analyzed using the AlphaLiquid®100-HRR panel. Plasma samples from a total of 87 patients were included in this study. Somatic mutations from cfDNA were detected in 78 (89.7%) patients, regardless of the presence of overt metastasis or concomitant treatment given at the time of plasma sample collection. Twenty-three patients were found to have known deleterious somatic or germline mutations in HRR genes from their cfDNA. Archival tissue samples from 33 (37.9%) patients were available for comparative analysis. Tissue sequencing was able to yield an NGS result in only 51.5% of the tissue samples. The general sensitivity of cfDNA for detecting somatic mutations in tissues was 71.8%, but important somatic/germline mutations in HRR genes were found to have a higher concordance (100%). Liquid biopsies can be a reasonable substitute for tissue biopsies in CRPC patients when evaluating genomic alterations.
... Various biomarkers that are involved in the therapeutic effects of ARATs have been reported in the literature (9). Expression of androgen receptor (AR) splice variant-7 in circulating tumour cells, pre-treatment tumour nuclear AR over-expression and CYP17 expression in the metastatic lesion, and over-expression of the Ets-related gene (ERG) which is an E26 transformation-specific transcription factor family member, have been reported as biomarkers that are involved in the therapeutic effects of ARATs (10,11). In clinical practice, it has been observed that the effect of the second agent is lower than the first agent when ARATs are administered consecutively due to cross-resistance between ARATs (12). ...
Background/aim:
Sarcopenia is a syndrome characterized by the progressive and generalized loss of skeletal muscle mass and has been reported to be a poor prognostic factor for taxane-treated castration-resistant prostate cancer (CRPC). However, whether sarcopenia affects androgen receptor axis-targeted therapies (ARATs) remains unknown. In the present study, we investigated the association between sarcopenia in CRPC and treatment outcomes of ARATs.
Patients and methods:
From January 2015 to September 2022, 127 patients who received ARATs as 1st-line treatment for CRPC at our two hospitals were included in the study. We retrospectively evaluated sarcopenia using computed tomography images and investigated whether sarcopenia affects the progression-free survival (PFS) and overall survival (OS) of patients with CRPC treated with ARATs.
Results:
Out of 127 patients, 99 were diagnosed with sarcopenia. The PFS of the sarcopenic group administered ARATs was significantly better than that of the non-sarcopenic group. Furthermore, in the multivariate analysis of PFS, sarcopenia was an independent favourable prognostic factor. However, there was no significant difference in the OS between the sarcopenic and non-sarcopenia groups.
Conclusion:
ARATs could more effectively treat patients with CRPC and sarcopenia than patients with CRPC without sarcopenia. Sarcopenia may positively influence the therapeutic effects of ARATs.
... However, it is also a therapeutic option for non-metastatic CRPC and metastatic hormone-sensitive PC (mH-SPC). Enzalutamide significantly increases the overall survival (OS) of CRPC patients and the time to PSA progression, but serious AEs like angina pectoris, left bundle branch block, acute myocardial infarction, sinus bradycardia, coronary artery thrombosis, myocardial ischemia and hypertension were noted in these patients [92][93][94]. In a meta-analysis (n = 8660) to study the cardiovascular toxicity of enzalutamide in PCa, the incidence of allgrade and high-grade hypertension in the enzalutamide-treated group was 10.5% and 4.8%, respectively, compared to 4.2% (all-grade) and 2.2% (high-grade) in the placebo-treated control group [11]. ...
Cardiovascular diseases (CVDs) and complications are often seen in patients with prostate cancer (PCa) and affect their clinical management. Despite acceptable safety profiles and patient compliance, androgen deprivation therapy (ADT), the mainstay of PCa treatment and chemotherapy, has increased cardiovascular risks and metabolic syndromes in patients. A growing body of evidence also suggests that patients with pre-existing cardiovascular conditions show an increased incidence of PCa and present with fatal forms of the disease. Therefore, it is possible that a molecular link exists between the two diseases, which has not yet been unraveled. This article provides insight into the connection between PCa and CVDs. In this context, we present our findings linking PCa progression with patients’ cardiovascular health by performing a comprehensive gene expression study, gene set enrichment (GSEA) and biological pathway analysis using publicly available data extracted from patients with advanced metastatic PCa. We also discuss the common androgen deprivation strategies and CVDs most frequently reported in PCa patients and present evidence from various clinical trials that suggest that therapy induces CVD in PCa patients.
... Moreover, bone biopsies often yield suboptimal samples for genomic evaluation, as they often produce an inadequate amount of viable tumor cells and the unique tissue processing procedures may decrease the analyzable DNA amount further (22,23). Other studies have reported biopsy failure rates higher than other cancer types, including a 31% failure rate in the biomarker-selected phase 3 trial PROfound (9,24,25). ...
Background:Assessment of genomic alterations in castration-resistant prostate cancer (CRPC) patients has become an important process for treatment decisions, but traditional tissue-based evaluation can be challenging.
Methods:To evaluate the clinical utility of liquid biopsy for the evaluation of genomic alterations in CRPC, we have prospectively collected plasma samples from patients being treated for clinically confirmed CRPC. The cell-free DNA (cfDNA) extracted from the plasma samples were analyzed using AlphaLiquid®100-HRR panel. Available archival tumor tissue samples were also collected and analyzed using the same panel.
Results:Plasma samples from a total of 87 patients were included in this study. Somatic mutations from cfDNA were detected in 78 (89.7%) of all 87 CRPC patients. Somatic mutations were detectable regardless of the presence of overt metastasis, or concomitant treatment given at the time of plasma sample collection. 23 patients were found to have known deleterious mutations in HRR genes from their cfDNA. 11 patients were additionally found to have possibly pathogenic mutations calculated by pathogenicity prediction algorithm. Archival tissue samples were available in 33 (37.9%) of the patients, 31 from prostate and 2 from metastatic bone lesions, collected a median of 2 years before the blood sample collection. Tissue sequencing was able to yield an NGS result in only 51.5% of the tissue samples. The general sensitivity of cfDNA for detecting somatic mutations discovered from tissues was 71.8%, but important somatic/germline mutations in HRR genes were found in higher concordance (100%).
Conclusions:Liquid biopsy can be a reasonable substitute for tissue biopsy in CRPC patients for evaluating genomic alterations.
... In PC, elevated androgen levels increase glucose uptake and upregulate the expression of GLUTs, implying a cross-talk between androgen signaling and glycolytic pathway, a mechanism that protects PC cells from glucose-deprivation-induced oxidative stress [287,288]. NF-κB-mediated GLUT1 overexpression and upregulated glucose metabolism are associated with enzalutamide resistance in PC [289,290]. In xenograft models of CRPC and enzalutamide-resistant PC patients, GLUT1 inhibition significantly reduced tumor volume and displayed synergistic effects with androgen receptor (AR)-targeted therapy [286]. ...
Cancer cells undergo metabolic reprogramming and switch to a ‘glycolysis-dominant’ metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the ‘Warburg effect,’ provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy.
... When enzalutamide is combined with radium-223, their effects in the bone microenvironment are prominent. Signs of enzalutamide resistance have been found in bone metastases of enzalutamide-treated patients, and the response to enzalutamide in the bone microenvironment is suggested to be dependent on the patient's androgen-signaling status [27]. Here, in the intratibial LNCaP xenograft model, the combination of radium-223 and enzalutamide resulted in decreased serum PSA levels and areas of tumor-induced abnormal bone, while either radium-223 or enzalutamide alone did not decrease serum PSA. ...
Radium-223 dichloride and enzalutamide are indicated for metastatic castration-resistant prostate cancer and their combination is currently being investigated in a large phase 3 clinical trial. Here, we evaluated the antitumor efficacy of radium-223, enzalutamide, and their combination in the intratibial LNCaP model mimicking prostate cancer metastasized to bone. In vitro experiments revealed that the combination of radium-223 and enzalutamide inhibited LNCaP cell proliferation and showed synergistic efficacy. The combination of radium-223 and enzalutamide also demonstrated enhanced in vivo antitumor efficacy, as determined by measuring serum PSA levels in the intratibial LNCaP model. A decreasing trend in the total area of tumor-induced abnormal bone was associated with the combination treatment. The serum levels of the bone formation marker PINP and the bone resorption marker CTX-I were lowest in the combination treatment group and markedly decreased compared with vehicle group. Concurrent administration of enzalutamide did not impair radium-223 uptake in tumor-bearing bone or the ability of radium-223 to inhibit tumor-induced abnormal bone formation. In conclusion, combination treatment with radium-223 and enzalutamide demonstrated enhanced antitumor efficacy without compromising the integrity of healthy bone. The results support the ongoing phase 3 trial of this combination.
... Increased expression of AR-v7, a constitutively activated splicing variant of AR, also impairs the efficacy of enzalutamide and abiraterone [8,9]. Glucocorticoid receptor (GR) expression also increases after enzalutamide treatment and sustains prostate cancer cell proliferation [10,11]. However, limited strategies have been developed to abrogate their activity [10,12]. ...
Strategies to degrade steroid receptors and their alternative splicing isoforms are critical for disease management. Here we report that celastrol recruited the ubiquitin ligase UBE3A and degraded androgen receptor (AR), AR-v7, and glucocorticoid receptor (GR) to suppress prostate cancer development. UBE3A was not an optimal endogenous AR ubiquitin ligase in mice and patients, but celastrol promoted the interaction between UBE3A and AR. Multiple domains of AR, including the DNA binding domain (DBD), were implicated into the UBE3A-AR interaction. Sharing a conserved DBD, GR, AR-v7, and other steroid receptors were recognized and degraded by UBE3A after celastrol treatment. Thus, celastrol suppressed prostate cancer cell proliferation more potently than enzalutamide. Modifying the carboxyl group of celastrol improved its anti-tumor activity. Together, our findings revealed that celastrol might be a potential molecular glue to enhance the interaction between UBE3A and steroid receptors to degrade multiple steroid receptors and splicing isoforms in prostate cancer, paving a way for further drug optimization and disease treatment.
... Immunohistochemical testing Immunohistochemistry (IHC) was performed, as previously described [18,28], on formalin-fixed, paraffin-embedded (FFPE) sections for N-terminal AR (dilution 1:50, Dako, Carpinteria, CA), GR (dilution 1:1300, BD Biosciences, San Jose, CA), C-terminal AR clone SP242 (dilution 1:500, LifeSpan Biosciences, Seattle, WA) and NKX3.1. Appropriate normal human FFPE tissue controls were used. ...
Background
Prostate cancer (PCa) typically spreads to the bone, and this distribution is attributed to the central role of the microenvironment in progression. However, metastasis to the adrenal glands, while not as common, does occur. The biology that accounts for adrenal metastases may be attributed to the unique local steroid metabolome and co-clinical characterization may elucidate the role steroid biosynthesis plays in PCa progression.
Methods
Three patients with metastatic PCa who had archived tumor tissue from an adrenalectomy were retrospectively identified, and one adrenal metastasis was developed into a xenograft (MDA-PCa-250). The adrenal metastases were characterized by performing somatic DNA whole exome sequencing (WES), RNA-Seq, immunohistochemistry (IHC), and steroid metabolite quantitation. The influence of steroid metabolites on adrenal metastasis cells and tumor growth was tested in vitro and in vivo.
Results
Clinically, adrenalectomy was performed during castration-resistant oligometastatic disease, and two men experienced resensitization to leuprolide. Somatic DNA WES revealed heterogeneous alterations in tumor suppressor and DNA damage repair pathway genes. Adrenal metastases had active androgen receptor (AR) signaling by IHC, and RNA-Seq supported a potential role for adrenal androgen precursor metabolism in activating the AR. Steroid quantitation suggested the adrenal androgen precursors were converted into testosterone in these metastases, and stable isotope tracing of an organoid from MDA-PCa-250 confirmed the capability of adrenal metastases to biosynthesize testosterone from adrenal precursors. In vitro testing of a cell line derived from MDA-PCa-250 showed that testosterone and cortisol stimulated tumor cell growth. In vivo experiments demonstrated that MDA-PCa-250 grew in intact mice with circulating testosterone, but not in castrated mice.
Conclusions
PCa adrenal metastases depend upon AR signaling driven by androgen precursors, androstenedione and dehydroepiandrosterone, available in the microenvironment, despite the presence of heterogeneous somatic DNA alterations. Moreover, MDA-PCa-250 provides a preclinical model that can recapitulate the unique androgen-dependence of adrenal metastases.
Clinical trial registration
This study does not report the clinical results of a clinical trial, but it does use samples from a completed clinical trial that is registered with clinicaltrials.gov (NCT01254864).
... In PROfound, 31% of patients' tumor tissue samples failed molecular screening (9,21). This is not unusual as biopsy failure rates between 25% and 75% have been reported for other studies involving genomic selection of patients, which potentially limits treatment decision making, especially in patients with mCRPC and non-accessible lesions (44)(45)(46). Although ctDNA screening methodology is still in its early stages, analysis of ctDNA has been used to characterize and monitor disease, as well as predict outcome and treatment response in several solid malignancies. ...
Purpose
Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study.
Experimental Design
Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®Liquid to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx.
Results
81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor.
Conclusions
We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.
... AR-V7 is the molecular marker for resistance in patients with bone metastatic CRPC [34,49,50]. We report here that interaction with preosteoblasts significantly upregulate AR-V7 transcript expression in prostate cancer cells. ...
Background
Bone metastatic prostate cancer does not completely respond to androgen-targeted therapy and generally evolves into lethal castration resistant prostate cancer (CRPC). Expression of AR-V7- a constitutively active, ligand independent splice variant of AR is one of the critical resistant mechanisms regulating metastatic CRPC. TNC is an extracellular matrix glycoprotein, crucial for prostate cancer progression, and associated with prostate cancer bone metastases. In this study, we investigated the mechanisms that regulate AR-V7 expression in prostate cancer cells interacting with osteogenic microenvironment including TNC.
Methods
Prostate cancer/preosteoblast heterotypical organoids were evaluated via immunofluorescence imaging and gene expression analysis using RT-qPCR to assess cellular compartmentalization, TNC localization, and to investigate regulation of AR-V7 in prostate cancer cells by preosteoblasts and hormone or antiandrogen action. Prostate cancer cells cultured on TNC were assessed using RT-qPCR, Western blotting, cycloheximide chase assay, and immunofluorescence imaging to evaluate (1) regulation of AR-V7, and (2) signaling pathways activated by TNC. Identified signaling pathway induced by TNC was targeted using siRNA and a small molecular inhibitor to investigate the role of TNC-induced signaling activation in regulation of AR-V7. Both AR-V7- and TNC-induced signaling effectors were targeted using siRNA, and TNC expression assessed to evaluate potential feedback regulation.
Results
Utilizing heterotypical organoids, we show that TNC is an integral component of prostate cancer interaction with preosteoblasts. Interaction with preosteoblasts upregulated both TNC and AR-V7 expression in prostate cancer cells which was suppressed by testosterone but elevated by antiandrogen enzalutamide. Interestingly, the results demonstrate that TNC-induced Src activation regulated AR-V7 expression, post-translational stability, and nuclear localization in prostate cancer cells. Treatment with TNC neutralizing antibody, Src knockdown, and inhibition of Src kinase activity repressed AR-V7 transcript and protein. Reciprocally, both activated Src and AR-V7 were observed to upregulate autocrine TNC gene expression in prostate cancer cells.
Conclusion
Overall, the findings reveal that prostate cancer cell interactions with the cellular and ECM components in the osteogenic microenvironment plays critical role in regulating AR-V7 associated with metastatic CRPC.
... Therefore, implementation of proteins as biomarkers has great potential. In a study, Eleni Efstathiou et al. found that the absence of AR-V7 in bone marrow biopsies from mCRPC correlated with better treatment response to enzalutamide (120). CRPC patients with AR-V7 positive CTCs were associated with resistance to enzalutamide and abiraterone (121,122). ...
Prostate cancer (PCa) is the most common cancer in men in the western world, but the lack of specific and sensitive markers often leads to overtreatment of prostate cancer which eventually develops into castration-resistant prostate cancer (CRPC). Novel protein markers for diagnosis and management of CRPC will be promising. In this review, we systematically summarize and discuss the expression pattern of emerging proteins in tissue, cell lines, and serum when castration-sensitive prostate cancer (CSPC) progresses to CRPC; focus on the proteins involved in CRPC growth, invasion, metastasis, metabolism, and immune microenvironment; summarize the current understanding of the regulatory mechanisms of emerging proteins in CSPC progressed to CRPC at the molecular level; and finally summarize the clinical applications of emerging proteins as diagnostic marker, prognostic marker, predictive marker, and therapeutic marker.
... Notably, early studies investigating the utility of AR-Vs focused primarily on transcriptomic and proteomic analysis of CTCs. AR-V7 (the most common splice variant) expression in CTCs of patients with mCRPCportends poor response to ARPI therapy[81][82][83][84] but not taxane chemotherapy.85,86 However, detection of AR-V7-positive CTCs does not completely preclude response to ARPI therapy41,87,88 and the apparent relationship between AR-V7 and disease burden and/ or prior treatment exposure may support use as a prognostic rather than predictive biomarker.41,89,90 ...
Background:
Genomic alterations to the androgen receptor (AR) are common in metastatic castration-resistant prostate cancer (mCRPC). AR copy number amplifications, ligand-binding domain missense mutations, and intronic structural rearrangements can all drive resistance to approved AR pathway inhibitors and their detection via tissue or liquid biopsy is linked to clinical outcomes. With an increasingly crowded treatment landscape, there is hope that AR genomic alterations can act as prognostic and/or predictive biomarkers to guide patient management.
Methods:
In this review, we evaluate the current evidence for AR genomic alterations as clinical biomarkers in mCRPC, focusing on correlative studies that have used plasma circulating tumor DNA to characterize AR genotype.
Results:
We highlight data that demonstrates the complexity of AR genotype within individual patients, and suggest that future studies should account for cancer clonal heterogeneity and variable tumor content in liquid biopsy samples. Given the potential for cooccurrence of multiple AR genomic alterations in the same or competing subclones of a patient, it is distinctly challenging to attribute blanket clinical significance to any individual alteration. This challenge is further complicated by the varied treatment exposures in contemporary patients, and the fact that AR genotype continues to evolve in the mCRPC setting across sequential lines of systemic therapy.
Conclusions:
As treatment access and liquid biopsy technology continues to improve, we posit that real-time measures of AR biology are likely to play a key role in emerging precision oncology strategies for metastatic prostate cancer.
... In the present work, we use DSRCT xenografts and patientderived tumor explants (PDXs) to extend the findings by Fine et al. to modern-day AR-targeted therapies, such as enzalutamide, that form the backbone of prostate cancer (PC) treatment 16 . In addition, we present promising efficacy data using an experimental AR-targeted antisense oligonucleotide (ASO) that significantly delayed tumor growth by suppressing AR expression. ...
Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.
... AR-Vs can be detected in normal prostate tissue and early stage tumors, yet their expression seems to increase in CRPCs suggesting an evolutionary advantage for more aggressive disease. AR-V7 is significantly over-expressed in antiandrogen resistant tumors [52,57,58] and its expression is associated with resistance to abiraterone and enzalutamide in two cohorts of CRPC patients [59,60] . This observation was recently confirmed in independent patients cohorts [61,62] . ...
The clinical behavior of prostate cancer is highly heterogeneous, with most patients diagnosed with localized disease that successfully responds to surgery or radiotherapy or that can be followed by active surveillance. However, a fraction of men will relapse after initial treatment and eventually progress to an aggressive resistant form with metastasis spreading and high mortality, a state referred to as castration resistant prostate cancer (CRPC). The technological advances in next generation sequencing have enabled the deep genomic and epigenomic characterization of both the hormone naïve and CRPC states, leading to the definition of molecular subclasses of prostate cancer that could inform the clinicians on therapeutic strategies. These studies also shed light on the mechanisms driving resistance to therapy. CRPCs adapt to androgen receptor (AR) signaling impairment - which follows first-line therapies as androgen deprivation or AR targeting - by restoring the nuclear receptor signaling by means of multiple mechanisms. Alternatively, tumor cells might become resistant to targeted therapies by exploiting lineage plasticity and activating alternative pathways. This review will discuss the main mechanisms leading to the emergence of resistance to therapy in prostate cancer patients in the context of genomic and molecular features of CRPC and on their causal role in the development of resistance.
... 26 Studies have observed an association of increased levels of AR variants with shorter survival endpoints and resistance to abiraterone and enzalutamide. 28,29 Of note, the prevalence of AR splice variant 7 mRNA (AR-V7) is low before therapy but increases with subsequent lines of treatment, 30 suggesting that there is little clinical value in determining the level of AR-V7 in the treatment-naive setting, and AR-V7 cannot be routinely recommended as a predictive biomarker for treatment selection in PC. 10 Furthermore, as previously mentioned, the AR signaling pathway requires stabilization of AR through binding to androgen ligands, whereas other steroid receptors are typically ubiquitinated and degraded by the proteasome. 31 This distinction led to the development of novel selective AR degraders that can target both wild-type AR and splice variants, raising the possibility for precision medicine in advanced PC. 31,32 Therapies targeting the aR signaling pathway Direct inhibition of AR with AR antagonists plus ADT rather than ADT alone has been postulated to result in complete blockade of the androgen signaling pathway and to lead to improved patient outcomes, thus spurring the development of AR antagonists to block AR or inhibit transcription of AR target genes. ...
... 26 Studies have observed an association of increased levels of AR variants with shorter survival endpoints and resistance to abiraterone and enzalutamide. 28,29 Of note, the prevalence of AR splice variant 7 mRNA (AR-V7) is low before therapy but increases with subsequent lines of treatment, 30 suggesting that there is little clinical value in determining the level of AR-V7 in the treatment-naive setting, and AR-V7 cannot be routinely recommended as a predictive biomarker for treatment selection in PC. 10 Furthermore, as previously mentioned, the AR signaling pathway requires stabilization of AR through binding to androgen ligands, whereas other steroid receptors are typically ubiquitinated and degraded by the proteasome. 31 This distinction led to the development of novel selective AR degraders that can target both wild-type AR and splice variants, raising the possibility for precision medicine in advanced PC. 31,32 Therapies targeting the aR signaling pathway Direct inhibition of AR with AR antagonists plus ADT rather than ADT alone has been postulated to result in complete blockade of the androgen signaling pathway and to lead to improved patient outcomes, thus spurring the development of AR antagonists to block AR or inhibit transcription of AR target genes. ...
Disclaimer
In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
Purpose
This article summarizes current androgen receptor (AR)–directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC).
Summary
PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone–releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRCPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR overexpression, and gene mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism or possess a higher affinity for AR and are not postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects.
Conclusion
Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.
... However, there were controvercial about the sequential or combined treatment strategy. The presence of a twocompartment, potentially adaptive, feedback loop in singleagent studies of androgen blockers suggests that combination therapies may eliminate adaptive responses between the respective drugs (Efstathiou et al., 2012;Efstathiou et al., 2015). Compared to traditional sequential therapies, a new drug is changed until the prodrug fails, they believe that simultaneous combination use may help improve patient outcomes (Attard et al., 2018;Efstathiou et al., 2020). ...
Objective: To summarize the current therapeutic status using chemotherapeutic agent docetaxel and endocrine therapeutic agents (ARAT, abiraterone, orteronel or enzalutamide) for the treatment of metastatic castration-resistant prostate cancer (mCRPC), including sequential therapy and combined therapy, to promote the consensus on the optimal regimen for achieving superior treatment efficacy.
Methods: Through literature search in PubMed, articles with the following relevant keywords were collected and anlyzed: CRPC, abiraterone, orteronel and enzalutamide, median survival, overall survival, prostate specific antigen (PSA), PSA response rate and median radiologic progression-free survival.
Results: Fifty-eight articles were obtained and analyzed in this review. These articles included androgen axis-targeting agents after docetaxel, docetaxel after androgen axis-targeting agents, Triple sequential and combination therapy, covering four current drugs for mCRPC treatment: docetaxel, abiraterone, orteronel, and enzalutamide. It was found that there may be some cross-resistance between androgen axis-targeting agents, which will reduce the efficacy of subsequent drug treatment. Although neither of the studies of using combination therapy showed serious drug toxicity, the efficacy of sequential therapy was not as good as expected. Most adverse reactions after treatment were reported to be level 1–2.
Conclusion: Based on the results of the current studies, abiraterone followed by enzalutamide treatment is the best sequential treatment for most docetaxel-naïve patients. This treatment achieves not only good OS, but also PFS and PSA response rates. In addition, for patients who have previously failed docetaxel treatment, enzalutamide is the best choice as the subsequent treatment.
... In the present work, we use DSRCT xenografts and patient-derived tumor explants (PDXs) to extend the findings by Fine et al. to modern-day AR-targeted therapies, such as enzalutamide, that form the backbone of prostate cancer treatment 16 . Additionally, we present promising efficacy data using an experimental AR-targeted antisense oligonucleotide (ASO) that significantly delayed tumor growth by suppressing AR expression. ...
Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have immediate clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.
ONE SENTENCE SUMMARY
We demonstrate that DSRCT, an aggressive pediatric cancer, is an AR-driven malignancy capable of responding to androgen deprivation therapy.
... Conversely, APA arm led to a clinically significant increase in testosterone levels, similar to what has been reported with enzalutamide alone in the same setting [13]. Interestingly, a prospective phase 2 study, including 60 patients with bone mCRPC who received enzalutamide 160 mg orally daily and had bone marrow biopsies before treatment and at 8 weeks of treatment have shown bone marrow and circulating testosterone levels increased, providing the first evidence in humans that enzalutamide suppresses AR signalling while inducing an adaptive feedback [28]. Nevertheless, the difference in testosterone levels with APA alone as compared to ADT plus AAP and APA plus AAP was not reflected in the overall HRQoL, which showed no difference among the three treatment arms. ...
Background
Androgen deprivation therapy (ADT) combined with apalutamide, abiraterone acetate plus prednisone, enzalutamide, or docetaxel are the standard treatments for advanced castration-sensitive prostate cancer (CSPC). We investigated ADT-free alternatives for advanced CSPC.
Patients and methods
LACOG 0415 is a phase 2, open-label, non-comparative, randomized trial. Patients with advanced CSPC were randomized (1:1:1) to receive goserelin plus abiraterone acetate and prednisone (ADT plus AAP arm), apalutamide (APA arm), or apalutamide plus abiraterone acetate and prednisone (APA plus AAP arm). The primary endpoint was the proportion of patients with PSA of ≤0.2 ng/mL at week 25 in the modified intention-to-treat population. Safety analyses were performed in all patients with at least one dose of the study drug.
Results
Of 128 randomized patients, 120 patients were evaluable for PSA response at week 25; 17.2% had a high-risk biochemical recurrence, 8.6% had locally advanced disease, and 74.2% had distant metastases. At week 25, PSA of ≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%–87.6%), 60.0% (95%CI 43.3%–75.1%), and 79.5% (95%CI 63.5%–90.7%) of patients in ADT plus AAP, APA, and APA plus AAP arms, respectively. PSA decline of ≥80% was observed in 100%, 90.0%, and 97.4%, respectively. Grade 3–4 AEs were observed in 31.0%, 21.4% and 36.4%, respectively. Testosterone levels increased significantly in the APA arm and decreased significantly in ADT plus AAP and APA plus AAP arms.
Conclusions
ADT-free alternatives provide a high PSA response in advanced CSPC, although the APA arm did not reach the expected rate of PSA of ≤0.2 ng/mL at week 25. These results warrant further investigation of ADT-free treatments as alternatives in advanced CSPC.
Source study registration
ClinicalTrials.gov NCT02867020.
... Bone specimens were decalcified and all samples formalin-fixed, paraffin-embedded as previously described [53]. Tissue sections were stained with anti-AR (N-terminal) antibody (#M3562 Clone AR441 1:50; Dako; Santa Clara, CA, USA), anti-ERG antibody (#CM421C Clone 9FY 1:50; Biocare Medical; Pacheco, CA, USA), anti-ACAT1 antibody (#HPA004428 1:500; Sigma; Darmstadt, Germany), anti-BDH1 antibody (#HPA030947 1:2000; Sigma), anti-OXCT1 antibody (#HPA012047 1:200; Sigma), anti-HMGCL antibody (#HPA004727 1:100; Sigma), anti-HMGCS2 antibody (#HPA027442 1:1750; Sigma) and anti-SLC16A7 antibody (#HPA005911 1:100; Sigma) as described elsewhere [54]. ...
Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.
... Pretreatment serum levels of testosterone or adrenal androgens were considered, but were modestly predictive of response to ADT [112][113][114][115]. At the molecular level, ADT response was associated with AR (variant) expression levels [116], length of AR CAG repeats that affect activity of AR [117,118], expression of steroidogenic enzymes targeted by ADT such as CYP17A1 [119], and germline polymorphisms in androgen transporters [120]. Expression status of two AR target genes, PSA and PSMA, in CaP circulating tumor cells, were used as a measure of AR activity and correlated with CaP response to ADT [121]. ...
Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR's transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients.
... We note that prior studies have demonstrated that leuprolide decreases tissue levels of androgen, and that abiraterone plus leuprolide lower levels even more dramatically [34,35]. However, when enzalutamide is used in addition to GnRH agonist therapy, tissue levels of androgen can rise [36]. One speculative hypothesis for the comparatively decreased odds of cardiac ADRs with enzalutamide is therefore that the higher levels of intracellular androgen are somehow cardioprotective. ...
Background
Androgen deprivation therapy (ADT) is standard-of-care for advanced prostate cancer. Studies have generally found increased cardiovascular risks associated with ADT, but the comparative risk of newer agents is under-characterized. We defined the cardiac risks of abiraterone and enzalutamide, using gonadotropic releasing hormone (GnRH) agonists to establish baseline ADT risk.
Methods
We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac adverse drug reactions (ADRs) in a cohort taking GnRH agonists, abiraterone, or enzalutamide therapy for prostate cancer, comparing them to all other patients. To examine the relationship, we used an empirical Bayes estimator to screen for significance, then calculated the reporting odds ratio (ROR), a surrogate measure of association. A lower bound of a 95% confidence interval (CI) of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance.
Findings
We identified 2,433 cardiac ADRs, with higher odds for abiraterone compared to all other VigiBase drugs for overall cardiac events (ROR 1•59, 95% CI 1•48—1•71), myocardial infarction (1•35, 1•16—1•58), arrythmia (2•04, 1•82—2•30), and heart failure (3•02, 2•60—3•51), but found no signal for enzalutamide. Patients on GnRH agonists also had increased risk of cardiac events (ROR 1•21, 95% CI 1•12—1•30), myocardial infarction (1•80, 1•61—2•03) and heart failure (2•06, 1•76—2•41).
Interpretation
We found higher reported odds of cardiac events for abiraterone but not enzalutamide. Our data may suggest that patients with significant cardiac comorbidities may be better-suited for therapy with enzalutamide over abiraterone.
Funding
None
Background
KI67 is a well‐known biomarker reflecting cell proliferation. We aim to elucidate the predictive role of KI67 in the efficacy of abiraterone for patients with advanced prostate cancer (PCa).
Methods
Clinicopathological data of 152 men with metastatic PCa, who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry using the prostate biopsy specimen. The predictive value of KI67 on the therapeutic efficacy of abiraterone was explored using Kaplan–Meier curve and Cox regression analysis. The endpoints included prostate‐specific antigen (PSA) progression‐free survival (PSA‐PFS), radiographic PFS (rPFS), and overall survival (OS).
Results
In total, 85/152 (55.9%) and 67/152 (44.1%) cases, respectively, received abiraterone at metastatic hormone‐sensitive (mHSPC) and castration‐resistant PCa (mCRPC) stage. The median KI67 positivity was 20% (interquartile range: 10%–30%). Overall, KI67 rate was not correlated with PSA response. Notably, an elevated KI67‐positive rate strongly correlated with unfavorable abiraterone efficacy, with KI67 ≥ 30% and KI67 ≥ 20% identified as the optimal cutoffs for prognosis differentiation in mHSPC (median PSA‐PFS: 11.43 Mo vs. 26.43 Mo, p < 0.001; median rPFS: 16.63 Mo vs. 31.90 Mo, p = 0.003; median OS: 21.77 Mo vs. not reach, p = 0.005) and mCRPC (median PSA‐PFS: 7.17 Mo vs. 12.20 Mo, p = 0.029; median rPFS: 11.67 Mo vs. 16.47 Mo, p = 0.012; median OS: 21.67 Mo vs. not reach, p = 0.073) patients, respectively. Multivariate analysis supported the independent predictive value of KI67 on abiraterone efficacy. In subgroup analysis, an elevated KI67 expression was consistently associated with unfavorable outcomes in the majority of subgroups. Furthermore, data from another cohort of 79 PCa patients with RNA information showed that those with KI67 RNA levels above the median had a significantly shorter OS than those below the median (17.71 vs. 30.72 Mo, p = 0.035).
Conclusions
This study highlights KI67 positivity in prostate biopsy as a strong predictor of abiraterone efficacy in advanced PCa. These insights will assist clinicians in anticipating clinical outcomes and refining treatment decisions for PCa patients.
Dysregulated transcription factor activity is a defining feature of various cancer types. As such, targeting oncogenic transcriptional dependency has long been pursued as a potential therapeutic approach. However, transcription factors have historically been deemed as undruggable targets due to their highly disordered structures and lack of well-defined binding pockets. Nevertheless, interest in their pharmacologic inhibition and destruction has not dwindled in recent years. Here, we discuss new small-molecule-based approaches to target various transcription factors. Ligands with different mechanisms of action, such as inhibitors, molecular glue degraders, and proteolysis targeting chimeras, have recently seen success preclinically and clinically. We review how these strategies overcome the challenges presented by targeting transcription factors.
Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Background:
Androgen receptor (AR) gene alterations, as detected by circulating tumor cell-free DNA (cfDNA) genomic profiling, have been shown to emerge after a variable duration of androgen signaling inhibition. AR alterations were associated with inferior outcomes on treatment with androgen receptor pathway inhibitors (ARPI) in the first line metastatic castration-resistant prostate cancer (mCRPC) setting in a phase 2 trial. Here in, we assessed the impact of these AR alterations on survival outcomes in a real-world patient population of mCRPC experiencing disease progression on an ARPI.
Methods:
In this IRB-approved retrospective study, consecutively seen patients with a confirmed diagnosis of mCRPC, with disease progression on a treatment with ARPIs in the first line mCRPC setting, with no prior exposure to an ARPI in the castration sensitive setting, and with available cfDNA profiling from a CLIA certified laboratory were included. Patients were categorized based on AR status: wild-type (ARwt ) or alteration-positive (AR+ ). The objective was to correlate overall survival (OS) after disease progression on the first-line ARPI with the presence or absence of AR alterations. Kaplan-Meier and Cox Regression Tests were used as implemented in R-Studio (v.4.2).
Results:
A total of 137 mCRPC patients were eligible: 69 with ARwt versus 68 with AR+ . The median OS posttreatment with the first ARPI was significantly higher for ARwt than AR+ patients (30.1 vs. 15.2 mos; p < 0.001). Of 108 patients who received a subsequent line of therapy, 63 received an alternate ARPI (AR+ 39 vs. 24 ARwt ), while 20 received a taxane-based therapy (11 AR+ vs. 9 ARwt ). Among patients receiving an alternate ARPI, AR+ had numerically shorter OS (16.8 vs. 30.4 mos, p = 0.1). Among patients receiving taxane-based regimens, the OS was not significantly different between AR+ and ARwt (14.5 vs. 10.1 mos, p = 0.18).
Conclusion:
In this real-world study, mCRPC patients with AR alterations on cfDNA had inferior OS after disease progression on the first ARPI, compared to those who did not, and may impact outcomes on a subsequent ARPI but not on subsequent taxane-based therapy received. By providing survival estimates for patients with or without AR alterations, our data may aid in patient counseling, prognostication, treatment decision, and for designing future clinical trials in this setting.
Testosterone and 5α–dihydrotestosterone acting through the androgen receptor (AR) direct virilization of the male fetus during embryogenesis, and the development of primary and secondary male sexual characteristics during puberty. During adulthood the AR signaling pathway is involved in maintaining the adult male phenotype, male reproduction, and functions of tissues such as bone and muscle.AR is a ligand activated transcription factor member of the nuclear receptor family of protein. It regulates transcription of a network of genes by recruiting coregulator complexes leading to chromatin reorganization, and histone modification at target genomic loci. Besides being involved with a spectrum of clinical conditions that include the syndromes of androgen insensitivity, a form of motor neuron disease known as spinal bulbar muscular atrophy and male infertility, abnormalities of AR signaling are also responsible for initiation, progression, and treatment resistance of prostate cancer.Thanks to the generation of transgenic animal models with conditional knock out of AR in a variety of target organs, it has been possible to recognize novel functions of AR signaling. Old and new aspects of AR physiopathology, together with emerging concepts on the role of AR signaling in females, breast cancer and polycystic ovarian disease, will be discussed in detail in this review.KeywordsAndrogen receptorMale reproductionFemale reproductionProstate cancerBreast cancerNuclear receptors
Purpose:
Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting.
Patients and methods:
Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments.
Results:
In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide v 34.2 [95% CI, 31.4 to 37.3] months for enzalutamide and AAP; hazard ratio [HR], 0.89; one-sided P = .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 [95% CI, 19.4 to 22.9] months for enzalutamide v 24.3 [95% CI, 22.3 to 26.7] months for enzalutamide and AAP; HR, 0.86; two-sided P = .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone.
Conclusion:
The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.
The title molecule, C23H26N2O4S, adopts a cup-shaped conformation. In the crystal, layers lying parallel to the ab plane are formed by C—H⋯O hydrogen bonds and C—H⋯π(ring) interactions. The layers stack along the c-axis direction through normal van der Waals interactions.
Purpose:
The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of ctDNA testing as an additional method to identify mCRPC patients with HRR gene alterations who may be eligible for olaparib treatment.
Patients and methods:
Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne® Liquid CDx test for BRCA1, BRCA2 (BRCA) and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM-alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A.
Results:
Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients' baseline demographics and characteristics, and the prevalence of HRR alterations were comparable to the Cohort A ITT population. rPFS was longer in the olaparib group versus control (median 7.4 vs. 3.5 months; hazard ratio [HR] 0.33; 95% confidence interval [CI], 0.21-0.53; nominal P < 0.0001), which is consistent with Cohort A ITT population (HR 0.34 [95% CI, 0.25-0.47]).
Conclusions:
When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.
Overview
Cancer of the prostate is the most commonly diagnosed nonskin neoplasm and the second leading cause of cancer‐related mortality in men in the United States. Considerable advances have been made in screening, diagnosis, and therapy options, particularly in advanced disease, but controversies about the diagnosis and management of prostate cancer, especially in the areas of screening and choice of therapy, continue to evolve. Research initiatives in advanced disease have shifted from prognostication to prediction, and current treatment considerations are focused on optimization of therapy sequence, development of rational combinations, biomarker‐driven patient selection, determining the role of local disease control in patients with metastases, and bone targeting therapies. Despite progress, prostate cancer survival has not improved at the same pace as other cancer subtypes. It is anticipated that addressing knowledge gaps will lead to the development of novel agents with unique mechanisms of action and optimization of integrated strategies (surgical, radiation, and medical) to improve overall survival.
Prostate cancer awareness, clinical application of improved biopsy schemes, and advances in imaging combined with the widespread use of prostate‐specific antigen (PSA) have resulted in increased detection of early prostate cancer. The question of whether PSA screening would reduce mortality from prostate cancer has now been tested in the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial first published in 2009. Though many of the apparent discrepancies between these trials can be accounted for by trial design and patient cross‐contamination, they brought to the forefront the dilemma of overdiagnosis and overtreatment, as well as the heterogeneous nature of prostate cancer and the urgent need to improve the accuracy of identifying clinically significant early disease with lethal potential. It is hoped that enhancing the current morphologic and anatomic classification of prostate cancer with a better understanding of the molecular underpinnings of diverse disease states will lead to a more refined taxonomy of prostate cancer and ultimately improve outcomes while minimizing treatment‐related morbidity.
Salient features that distinguish prostate cancer from other malignancies and frame the dilemmas surrounding it are its striking age‐dependent incidence, with progressively increasing frequency with increasing age, a strong familial and hereditary component, the variable lethality of morphologically identical cancers, the central role of androgen signaling, the preponderance of bone‐forming metastases, and metabolic derangements contributing to lethal progression. Important advances made in each of these areas will modify the approaches currently used to prevent, prognosticate, predict, and treat prostate cancer.
Despite newer therapies for castrate-resistant prostate cancer (CRPC), many patients do not experience a treatment response, and most eventually experience secondary resistance. Various androgen-receptor-related and alternative mechanisms of resistance in CRPC have been identified. This focus on understanding the molecular basis of therapeutic resistance, including lineage plasticity, neuroendocrine transformation, and a range of other implicated genomic alterations will hopefully inform decision-making in the care of this lethal cancer.
Therapeutic interventions for advanced castration-resistant prostate cancer (CRPC) are focused on inhibiting the androgen receptor (AR) through targeting of its C-terminal ligand binding domain (LBD). However, a significant subset of CRPC patients demonstrate primary resistance to androgen deprivation and anti-androgen therapies, suggesting that other targets, outside of the AR, might be pertinent to the cancer progression. One explanation is the expression of androgen receptor splice variants (AR-Vs). So far, more than 20 AR-Vs have been identified from both prostate cancer cell lines and prostate cancer tissue biopsies. Most of the AR-Vs have a conserved N-terminal domain, but lack the LBD, yet retain the ability to bind DNA and activate downstream signaling. Although it remains unclear whether AR-Vs are principal divers or mere bystanders of CRPC progression, inhibiting AR-Vs, through drugs that target the AR transactivation function outside of the LBD, has been a major emphasis for next generation therapeutics in prostate cancer. This book chapter is dedicated to the role of AR variants and their clinical importance. We will review the initial discovery of AR-Vs, their regulation and prevalence, as well as their biological function in prostate cancer. We will provide an overview of the role of AR-Vs in the development of metastatic CRPC and in promoting clinical treatment failures. Lastly, we will present an introduction to the therapeutic approaches towards developing AR-V-targeted therapies including the continuing progress, the old challenges, and the new prospects.
Prostate cancer (PCa) is among the leading malignancies in men worldwide. Despite multiple available therapeutic strategies, metastatic PCa is often incurable. Androgens and androgen receptors (AR) have been shown to play critical roles in PCa development and progression. Androgen deprivation therapy has been a mainstay in PCa treatment options. Upon androgen deprivation, most cancer cells die; however, some survive by adopting strategies that rekindle the AR axis. The AR, a ligand-induced transcription factor, modulates the expression of multiple target genes involved in cell proliferation and survival. To compensate for androgen absence, the AR is overexpressed in PCa, both at RNA and protein levels, via gene amplification as well as post-transcriptional regulations. The multiple splice variants of AR (ARSVs) are reported to be generated via genome rearrangement and alternate splicing. These are clinically relevant as most of these lack ligand-binding domain, and therefore, facilitate ligand-independent AR activity. These also have the ligand-independent ability to translocate and exhibit activity in the nucleus leading to the androgen signaling axis being active despite androgen removal. Among the splice variants, ARV7 is one of the most prominent and a potential clinical biomarker for metastatic castration-resistant PCa. Despite multiple treatment options, PCa often ends up developing resistance. Strategies rooted in RNA-based regulation have been found helpful in mitigating the disease. The antisense nucleic acid-based strategies or miRNA mimics are therapeutically promising and can foster new therapeutic regimens. However, these are still under clinical development. In conclusion, the ARSVs and AR-mediated strategies have immense therapeutic potential which is highlighted here to offer a novel paradigm toward development on clinical platforms.
The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.
Background
The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC.
Methods
ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.
Findings
982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plus abiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5–58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7–27·5) versus 16·6 months (13·9–19·3; HR 0·70, 95% CI 0·60–0·83; p<0·0001). The most common grade 3–4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone–prednisone and 49 [10%] of 489 receiving abiraterone–prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone–prednisone and 181 (37%) patients receiving abiraterone–prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone–prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone–prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death).
Interpretation
Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC.
Funding
Janssen Research & Development.
Le récepteur des androgènes (RA) est la principale cible thérapeutique du cancer de la prostate (CaP) métastatique. Bien que cette thérapie soit initialement efficace, les effets sont transitoires. De nombreux mécanismes peuvent expliquer la progression du CaP vers un stade de résistance à la castration, telles les modifications du RA. Des données récentes ont montré que les variants constitutifs RA-Q641X et RA-V7, caractérisés par la perte du domaine de liaison au ligand, étaient associés à l’expression de marqueurs mésenchymateux. L’étude de la régulation de la N-cadhérine a mis en évidence que si le RA sauvage et les variants constitutifs se liaient tous deux aux éléments de réponse du gène codant, seuls les derniers étaient associés à une augmentation de l’acétylation de l’histone H4, marque positive de la transcription. Le RNA-seq a révélé que leur expression était aussi corrélée à la régulation de sets de gènes spécifiques incluant des facteurs de transcription dont certains ont déjà été caractérisés en cancérologie.En ce qui concerne le RA-T576A, porteur d’une mutation faux-sens, les données ont révélé une séquence consensus de liaison à l’ADN moins conservée pour le RA sauvage que pour ce mutant et l’importance du 11ème nucléotide des éléments de réponse. De plus, cette mutation a semblé impacter le transcriptome du RA. Ce travail met en évidence le comportement distinct des variants du RA et aide à mieux comprendre leurs modes d’action en décrivant leurs activités transcriptionnelles.
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group.
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).
Mechanisms mediating androgen receptor (AR) reactivation in prostate cancer (PCa) that progresses after castration (castration-resistant prostate cancer, CRPC) and subsequent treatment with abiraterone (CYP17A1 inhibitor that further suppresses androgen synthesis) remain unclear.
PCa xenografts were examined to identify mechanism of progression after castration and abiraterone.
AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens or alterations in AR co-regulators. In contrast, mRNA encoding full length AR (AR-FL) and a constitutively active splice variant (AR-V7) were increased compared to xenografts prior to castration, with an increase in AR-V7 relative to AR-FL. This shift towards AR-V7 was due to a feedback mechanism whereby the androgen-liganded AR stimulates expression of proteins that suppress generation of AR-V7 relative to AR-FL transcripts. However, despite the increases in AR-V7 mRNA, it remained a minor transcript (<1%) relative to AR-FL in resistant VCaP xenografts and CRPC clinical samples. AR-V7 protein expression was similarly low relative to AR-FL in castration-resistant VCaP xenografts and androgen-deprived VCaP cells, but the weak basal AR activity in these latter cells was further repressed by AR-V7 siRNA.
AR-V7 at these low levels is not adequate to restore AR activity, but its rapid induction after androgen deprivation allows tumors to retain basal AR activity that may be needed for survival until more potent mechanisms emerge to activate AR. Agents targeting AR splice variants may be most effective when used very early in conjunction with therapies targeting the AR ligand binding domain.
Enzalutamide is a novel antiandrogen which is approved for the treatment of metastatic, castration-resistant prostate cancer (mCRPC) after taxane-based chemotherapy. The efficacy of enzalutamide after the sequence docetaxel and abiraterone is not proven.
Thirty-five mCRPC patients in the German compassionate use program, who received enzalutamide after progression with taxane-based chemotherapy and abiraterone were prospectively evaluated. The endpoints of the study were overall survival, radiologic progression-free survival and safety.
The median treatment duration on enzalutamide was 2.8 months. The median overall survival was 7.5 months [95% confidence interval (CI) 4.7-10.3] while median progression-free survival assessed by imaging was 3.1 months (95% CI 1.4-4.8). The most common toxicities of all grades were anemia and weight loss.
Although the results are limited by a small patient number, the consecutive use of enzalutamide and abiraterone after taxane-based chemotherapy shows a modest clinical activity. Thus, sequence therapy alternating between chemotherapy and antihormonal drugs might be a more promising approach in mCRPC treatment.
The metabolic functions of androgen receptor (AR) in normal prostate are circumvented in prostate cancer (PCa) to drive tumor growth, and the AR also can acquire new growth-promoting functions during PCa development and progression through genetic and epigenetic mechanisms. Androgen deprivation therapy (ADT, surgical or medical castration) is the standard treatment for metastatic PCa, but patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC). Early studies from many groups had shown that AR was highly expressed and transcriptionally active in CRPC, and indicated that steroids from the adrenal glands were contributing to this AR activity. More recent studies showed that CRPC cells had increased expression of enzymes mediating androgen synthesis from adrenal steroids, and could synthesize androgens de novo from cholesterol. Phase III clinical trials showing a survival advantage in CRPC for treatment with abiraterone (inhibitor of the enzyme CYP17A1 required for androgen synthesis that markedly reduces androgens and precursor steroids) and for enzalutamide (new AR antagonist) have now confirmed that AR activity driven by residual androgens makes a major contribution to CRPC, and led to the recent Food and Drug Administration approval of both agents. Unfortunately, patients treated with these agents for advanced CRPC generally relapse within a year and AR appears to be active in the relapsed tumors, but the molecular mechanisms mediating intrinsic or acquired resistance to these AR-targeted therapies remain to be defined. This review outlines AR functions that contribute to PCa development and progression, the roles of intratumoral androgen synthesis and AR structural alterations in driving AR activity in CRPC, mechanisms of action for abiraterone and enzalutamide, and possible mechanisms of resistance to these agents.Oncogene advance online publication, 10 June 2013; doi:10.1038/onc.2013.235.
Background:
Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy.
Methods:
In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival.
Results:
The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone.
Conclusions:
Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; ClinicalTrials.gov number, NCT00887198.).
The androgen receptor (AR) is a key molecule in prostate cancer and Kennedy's disease. Understanding the regulatory mechanisms of this steroid receptor is important in the development of potential therapies for these diseases. One layer of AR regulation is provided by post-translational modifications including phosphorylation, acetylation, sumoylation, ubiquitination and methylation. While these modifications have mostly been studied as individual events, it is becoming clear that these modifications can functionally interact with each other in a signalling pathway. In this review, the effects of all modifications are described with a focus on interplay between them and the functional consequences for the AR.
Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow-infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations.
This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral abiraterone acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues.
Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression.
The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that abiraterone acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone.
Introduction:
An increasing number of basic, translational and clinical studies demonstrate the importance of the protein tyrosine kinase receptor, c-Met, in the progression of prostate cancer. c-Met is overexpressed in primary prostate cancers, further increased in expression in bone metastases and is associated with the development of castrate-resistant disease. Because of its importance as a target, c-Met inhibitors have reached clinical trial for advanced, castrate-resistant prostate cancer.
Areas covered:
In this review, altered expression of c-Met and hepatocyte growth factor in prostate tumors and the microenvironment and how they contribute to growth and invasion of prostate cancer cells is described. Next, preclinical studies providing the support for use of c-Met inhibitors are discussed. Finally, early promising results from c-Met inhibitors in clinical trial, and future prospects for c-Met inhibitors in the treatment of advanced stage prostate cancer, are discussed.
Expert opinion:
An emerging theme in treating metastatic prostate cancer is the requirement to target both the epithelial and stromal compartments. Results from clinical trials suggest that inhibitors of c-Met that block stromal-mediated c-Met activation in prostate tumors may be important therapeutic agents in at least a subset of patients with metastatic prostate cancer. However, as many of the inhibitors have multiple targets, the efficacy of targeting c-Met alone remains to be determined.
To summarize recent advances in androgen biosynthesis and metabolism in peripheral tissues (e.g., liver and prostate) and how these can be exploited therapeutically.
Human liver catalyzes the reduction of circulating testosterone to yield four stereoisomeric tetrahydrosteroids. Recent advances have assigned the enzymes responsible for these reactions and elucidated their structural biology. Data also suggest that for 5alpha-dihydrotestosterone (5alpha-DHT), conjugation reactions (phase II) may precede ketosteroid reduction (phase I) reactions. Human prostate is the site of benign prostatic hyperplasia and prostate cancer, which occur in the aging male. Although the importance of local androgen biosynthesis in these diseases is accepted, recent advances have identified enzymes that regulate ligand access to the androgen-receptor; a 'backdoor pathway' to 5alpha-DHT that does not require testosterone acting as an intermediate; and the finding that castrate-resistant prostate cancer (CRPC) has undergone an adaptive response to androgen deprivation, which involves intratumoral testosterone and 5alpha-DHT biosynthesis that can be targeted using inhibitors of (CYP17-hydroxylase/17,20-lyase), aldo-keto reductase 1C3, and 5alpha-reductase type 1 and type 2.
Enzyme isoforms responsible for the biosynthesis and metabolism of androgens in liver and prostate have been identified and those responsible for the biosynthesis of androgens in CRPC can be therapeutically targeted.
Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive
form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here
we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens
that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor
with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation,
and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available
and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated
with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of
prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment
of advanced prostate cancer.
Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen-independent. High levels of expression of androgen receptor and androgen receptor-regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence.
Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied. Androgen receptor expression was measured using monoclonal antibody and automated digital video image analysis. Tissue androgens were measured using radioimmunoassay.
Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer (mean optical density, 0.284 +/- SD 0.115 and percentage positive nuclei, 83.7 +/- 11.6) was similar to benign prostate (mean optical density, 0.315 +/- 0.044 and percentage positive nuclei, 77.3 +/- 13.0). Tissue levels of testosterone were similar in recurrent prostate cancer (2.78 +/- 2.34 pmol/g tissue) and benign prostate (3.26 +/- 2.66 pmol/g tissue). Tissue levels of dihydrotestosterone, dehydroepiandrosterone, and androstenedione were lower (Wilcoxon, P = 0.0000068, 0.00093, and 0.0089, respectively) in recurrent prostate cancer than in benign prostate, and mean dihydrotestosterone levels, although reduced, remained 1.45 nM. Androgen receptor activation in recurrent prostate cancer was suggested by the androgen-regulated gene product, prostate-specific antigen, at 8.80 +/- 10.80 nmol/g tissue.
Testosterone and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor. Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue.
The Ki-67 staining index (Ki67-SI) has been associated with prostate cancer patient outcome; however, few studies have involved radiotherapy (RT) -treated patients. The association of Ki67-SI to local failure (LF), biochemical failure (BF), distant metastasis (DM), cause-specific death (CSD) and overall death (OD) was determined in men randomly assigned to short term androgen deprivation (STAD) + RT or long-term androgen deprivation (LTAD) + RT.
There were 537 patients (35.5%) on Radiation Therapy Oncology Group (RTOG) 92-02 who had sufficient tissue for Ki67-SI analysis. Median follow-up was 96.3 months. Ki67-SI cut points of 3.5% and 7.1% were previously found to be related to patient outcome and were examined here in a Cox proportional hazards multivariate analysis (MVA). Ki67-SI was also tested as a continuous variable. Covariates were dichotomized in accordance with stratification and randomization criteria.
Median Ki67-SI was 6.5% (range, 0% to 58.2%). There was no difference in the distribution of patients in the Ki-67 analysis cohort (n = 537) and the other patients in RTOG 92-02 (n = 977) by any of the covariates or end points tested. In MVAs, Ki67-SI (continuous) was associated with LF (P =.08), BF (P =.0445), DM (P <.0001), CSD (P <.0001), and OD (P =.0094). When categoric variables were used in MVAs, the 3.5% Ki67-SI cut point was not significant. The 7.1% cut point was related to BF (P =.09), DM (P =.0008), and CSD (P =.017). Ki67-SI was the most significant correlate of DM and CSD. A detailed analysis of the hazard rates for DM in all possible covariate combinations revealed subgroups of patients treated with STAD + RT that did not require LTAD.
Ki67-SI was the most significant determinant of DM and CSD and was also associated with OD. The Ki67-SI should be considered for the stratification of patients in future trials.
Disruption of stromal-epithelial interactions favoring prostate cancer progression may affect the phenotype of the disease. We did a preoperative study to test the hypothesis that thalidomide, an active agent in metastatic disease, is a modulator of the tumor microenvironment.
Eighteen men with high-risk prostate cancer were given thalidomide at doses escalated to 600 mg for 12 weeks, followed by radical prostatectomy. We constructed tissue microarrays from prostatectomy specimens from 15 treated patients and 15 matched untreated control subjects to assess effects of thalidomide on the tumor microenvironment. We compared the immunohistochemical expression of three groups of markers linked to angiogenesis, stromal-epithelial interactions, or the epithelial compartment. Levels of circulating basic fibroblast growth factor, interleukin-6, tumor necrosis factor-alpha, and vascular endothelial growth factor were also assessed.
Thalidomide was well tolerated and induced a median reduction in prostate-specific antigen of 41% without affecting testosterone. Tissue microarray analyses indicated modulation of vascular marker expression accompanied by a reduction in microvessel density in the treated group. Comparison of broader stromal-epithelial interaction markers between treated and control groups suggested a transition to a less aggressive phenotype as a result of thalidomide treatment. Hedgehog signaling was attenuated and the ratio of matrix metalloproteinases to E-cadherin shifted to favor E-cadherin. No differences were noted in proliferation or apoptosis in the epithelial compartment.
These findings are the first clinical evidence to support the hypothesis that the reported thalidomide clinical efficacy is attributable to early modulation of the tumor microenvironment and suggest that stromal-targeting therapies will be effective against prostate cancer.
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
Background: Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. Methods: We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. Results: After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate?prednisone group than in the placebo?prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate?prednisone group than in the placebo?prednisone group. Conclusions: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.
The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.
Prostate tumors develop resistance to androgen deprivation therapy (ADT) involving multiple mechanisms, one of which is expression of the constitutively active androgen receptor (AR) splice variants, which lack the ligand-binding domain. AR-V7 is the most abundantly expressed of the constitutively active AR-splice variants. In the VCaP human prostate cancer cell line as well as several human prostate cancer xenografts that do not have intragenic AR gene rearrangements, AR-V7 is expressed in response to ADT, suggesting that AR-splicing may occur in association with AR gene transcription initiation and elongation rate. Inhibition of transcription in VCaP cells was examined using actinomycin D (ActD), benzimidazole (DRB) or trichostatin A (TSA). ActD and DRB eliminated, while TSA weakened, ADT's capability in inducing AR full-length (ARfl) and AR-V7 mRNA, indicating association of AR-splicing with AR gene transcription initiation and elongation rate. The decision as to which splicing site is excised is determined by both the regulatory RNA sequences (cis-elements) and their associated RNA splicing proteins (trans-elements). Using chromatin immunoprecipitation (ChIP) assays with primers amplifying pre-mRNA regions that correspond to the 5’ and 3’ splice regions for ARfl and AR-V7 we identified trans-splicing elements recruited by ADT as well as ADT induced recruitment of U1A, U2AF, ASF/SF2 and p54nrb to intron splice sites for generation of AR-V7. Similar recruitment of these splicing factors to the splice sites was not seen in LNCaP cells in which ADT does not increase AR-V7. To locate potential RNA sequences (cis-elements) that are responsible for AR-V7 splicing, we screened exon 3B and its flanking region using the Splicing Rainbow and ESEfinder 3.0 programs. One intronic splicing enhancer (ISE) and one exonic splicing enhancer (ESE) near the 3’ss of exon 3B were identified. Pull-down assays with oligos for the ISE demonstrated binding to hnRNP I and U2AF65, while the ESE bound ASF/SF2. The activity of these two motifs was confirmed using an AR-V7 minigene. When the various splicing motifs were mutated, AR-V7 was not generated. These RNA-protein interactions are also regulated by ADT. siRNA knock-down of hnRNP I, U2AF65, and ASF/SF2 suppressed AR-V7 expression in VCaP cells in response to ADT. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-7 levels detected in prostate cancer cells.
Pacific Northwest Prostate Cancer SPORE, National Cancer Institute (XD and SRP); Canadian Institute of Health Research (XD, MOP-97934); Department of Defense plus Veterans Administration Grants (SRP).
Citation Format: Xeusen Dong, Liangliang Liu, Ning Xie, Shihua Sun, Stephen R. Plymate. Mechanisms of androgen receptor splicing in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4082. doi:10.1158/1538-7445.AM2013-4082
Abiraterone, an androgen synthesis inhibitor, has been successfully used in the treatment of castration-resistant prostate cancer (CRPC) for 2 yr. Enzalutamide is a second-generation nonsteroidal antiandrogen that has recently been approved for the same indication.
This is the first study to evaluate the effectiveness of enzalutamide after failure of abiraterone.
Thirty-five patients were identified as having received sequential therapy with abiraterone followed by enzalutamide. All patients had undergone prior docetaxel chemotherapy, and no patient had received ketoconazole.
Posttreatment changes in prostate-specific antigen (PSA) were used to determine the activity of enzalutamide in patients who had received prior abiraterone.
The median duration of abiraterone treatment was 9.0 mo (range: 2.0-19.0 mo). Of the 35 patients, 16 (45.7%) achieved a >50% decline in PSA, and 14 (40%) had a rising PSA as the best response. The median duration of subsequent enzalutamide treatment was 4.9 mo (Kaplan-Meier estimate; 95% confidence interval [CI], 2.4-7.4). Seven of 16 CRPC patients who were initially abiraterone-sensitive (43.8%) and 3 of 19 CRPC patients who were initially abiraterone-insensitive (15.8%) showed a >50% PSA decline while taking enzalutamide. Of the 35 patients, 17 (48.6%) were primarily enzalutamide-resistant and showed a rising PSA as the best response. Median time to progression was 4.0 mo (95% CI, 2.0-6.0) for 18 of 35 patients with at least one declining PSA value while taking enzalutamide (51.4%). Of the 17 patients who were assessable radiologically, only 1 (2.9%) attained a confirmed partial response. Small sample size was the major limitation.
Enzalutamide treatment achieved only a modest response rate in patients progressing after abiraterone. Although cross-resistance between abiraterone and enzalutamide was a common phenomenon, it was not inevitable, and a small but significant number of patients showed significant benefit from sequential treatment.
Objectives: To evaluate the efficacy, tolerability, endocrinological effects and the pharmacokinetics of CasodexTM, when given as monotherapy during daily dosing of 10–200 mg to patients with advanced prostate cancer. Methods: A total of 390 patients with advanced prostate cancer were treated for a minimum of 12 weeks with a daily monotherapy dose of Casodex. The doses ranged from 10 to 200 mg. Objective assessments of efficacy included: review of measurable metastases, prostate dimension, prostatic acid phosphatase and prostate-specific antigen (PSA) levels. Subjective assessments of efficacy included review of urological symptoms, performance status, bone scan and analgesic requirement. Pharmacokinetic samples were taken at various time points up to 3 months, and assayed using an achiral HPLC method. Results: Clear objective responses were observed, particularly at doses of 50 mg and above. Specifically, the median percentage decrease in PSA at 50 mg was 90.0%, and at 100 and 200 mg it was 93.4 and 94.8%, respectively. Up to 53% of symptomatic patients demonstrated a subjective response at 3 months. Casodex was well tolerated at all doses with no effect on haematological or cardiovascular parameters and no effect on renal function. The expected pharmacological effects of potent antiandrogen therapy, such as breast tenderness (58%), gynaecomastia (48%), and hot flushes (17%), were reported, but these incidences reflected the direct eliciting of these events. The intrinsic efficacy of Casodex was demonstrated despite increases of 60% in testosterone levels. However, this increase reached a plateau after 4–12 weeks of therapy, but the majority of values remained within the normal range. Casodex has a half-life of approximately 1 week, enabling once-daily dosing with no effect of age or renal impairment on its pharmacokinetics. Conclusion: Casodex has a favourable side effect profile compared with the known safety profiles of other antiandrogens and has demonstrated intrinsic efficacy. Casodex warrants further investigation as a monotherapy for the management of advanced prostate cancer.
Unlabelled:
Despite the impressive clinical activity of the second-generation antiandrogens enzalutamide and ARN-509 in patients with prostate cancer, acquired resistance invariably emerges. To identify the molecular mechanisms underlying acquired resistance, we developed and characterized cell lines resistant to ARN-509 and enzalutamide. In a subset of cell lines, ARN-509 and enzalutamide exhibit agonist activity due to a missense mutation (F876L) in the ligand-binding domain of the androgen receptor (AR). AR F876L is sufficient to confer resistance to ARN-509 and enzalutamide in in vitro and in vivo models of castration-resistant prostate cancer (CRPC). Importantly, the AR F876L mutant is detected in plasma DNA from ARN-509-treated patients with progressive CRPC. Thus, selective outgrowth of AR F876L is a clinically relevant mechanism of second-generation antiandrogen resistance that can potentially be targeted with next-generation antiandrogens.
Significance:
A missense mutation in the ligand-binding domain of the androgen receptor F876L confers resistance to the second-generation antiandrogens enzalutamide and ARN-509 in preclinical models of AR function and prostate cancer and is detected in plasma DNA from ARN-509-treated patients with progressive disease. These results chart a new path for the discovery and development of next-generation antiandrogens that could be coupled with a blood-based companion diagnostic to guide treatment decisions.
Persistent androgen receptor (AR) transcriptional activity underlies resistance to AR-targeted therapy and progression to lethal castration resistant prostate cancer (CRPC). Recent success in re-targeting persistent AR activity with next-generation androgen/AR axis inhibitors such as enzalutamide (MDV3100) has validated AR as a master regulator during all stages of disease progression. However, resistance to next-generation AR inhibitors limits therapeutic efficacy for many patients. One emerging mechanism of CRPC progression is AR gene rearrangement, promoting synthesis of constitutively-active truncated AR splice variants (AR-Vs) that lack the AR ligand binding domain. In this study, we demonstrate that cells with AR gene rearrangements expressing both full-length and AR-Vs are androgen-independent and enzalutamide-resistant. However, selective knock-down of AR-V expression inhibited androgen-independent growth and restored responsiveness to androgens and antiandrogens. In heterogeneous cell populations, AR gene rearrangements marked individual AR-V-dependent cells that were resistant to enzalutamide. Gene expression profiling following knock-down of full-length AR or AR-Vs demonstrated that AR-Vs drive resistance to AR-targeted therapy by functioning as constitutive and independent effectors of the androgen/AR transcriptional program. Further, mitotic genes deemed previously to be unique AR-V targets were found to be biphasic targets associated with a proliferative level of signaling output from either AR-Vs or androgen-stimulated AR. Overall, these studies highlight AR-Vs as key mediators of persistent AR signaling and resistance to the current arsenal of conventional and next-generation AR-directed therapies, advancing the concept of AR-Vs as therapeutic targets in advanced disease.
Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy.
In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival.
The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide.
Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.).
Dominant mutations or DNA amplification of tyrosine kinases are rare among the oncogenic alterations implicated in prostate cancer. We demonstrate that castration-resistant prostate cancer (CRPC) in men exhibits increased tyrosine phosphorylation, raising the question of whether enhanced tyrosine kinase activity is observed in prostate cancer in the absence of specific tyrosine kinase mutation or DNA amplification. We generated a mouse model of prostate cancer progression using commonly perturbed non-tyrosine kinase oncogenes and pathways and detected a significant up-regulation of tyrosine phosphorylation at the carcinoma stage. Phosphotyrosine peptide enrichment and quantitative mass spectrometry identified oncogene-specific tyrosine kinase signatures, including activation of EGFR, ephrin type-A receptor 2 (EPHA2), and JAK2. Kinase:substrate relationship analysis of the phosphopeptides also revealed ABL1 and SRC tyrosine kinase activation. The observation of elevated tyrosine kinase signaling in advanced prostate cancer and identification of specific tyrosine kinase pathways from genetically defined tumor models point to unique therapeutic approaches using tyrosine kinase inhibitors for advanced prostate cancer.
Genetic aberrations affecting the androgen receptor (AR) are rare in untreated prostate cancers (PCs) but have been found in castration-resistant prostate cancers (CRPCs). Further, successful treatment with novel endocrine therapies indicates that CRPCs remain androgen-sensitive. Known AR aberrations include amplification of the AR gene leading to the overexpression of the receptor, point mutations of AR resulting in promiscuous ligand usage, and constitutively active AR splice variants. Gain, or amplification, of the AR gene is one of the most frequent genetic alterations observed in CRPCs. Up to 80% of CRPCs have been reported to carry an elevated AR gene copy number, and about 30% have a high-level amplification of the gene. AR mutations are also commonly observed and have been found in approximately 10-30% of the CRPC treated with antiandrogens; however, the frequency and significance of AR splice variants is still unclear. Because AR aberrations are found almost exclusively in CRPC, these alterations must have been selected for during therapy. Interestingly, these aberrations lead to activation of the receptor, despite treatment-induced emergence of therapy-resistant tumor clones. Therefore, future novel treatment strategies should focus on suppressing AR activity in CRPC.
MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease.
This phase 1-2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718.
We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased (18)F-fluoro-5alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34-not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction.
We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease.
Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium.
Efficacy equivalent to that reported in other common adult solid tumors considered to be chemotherapy-sensitive has been reported with Docetaxel in patients with castrate-resistant prostate cancer. However, in contrast to other cancers, the expected increase in efficacy with the use of chemotherapy in earlier disease states has not been reported to date in prostate cancer. On the basis of these observations, we speculated that the therapy development paradigm used successfully in other cancers may not apply to the majority of prostate cancers. Several lines of supporting clinical and experimental observations implicate the tumor microenvironment in prostate carcinogenesis and resistance to therapy. We conclude that a foundation to guide the development of therapy for prostate cancer is required. The therapy paradigm we propose accounts for the central role of the tumor microenvironment in bone and, if correct, will lead to microenvironment-targeted therapy.
To evaluate the efficacy, tolerability, endocrinological effects and the pharmacokinetics of Casodex, when given as monotherapy during daily dosing of 10-200 mg to patients with advanced prostate cancer.
A total of 390 patients with advanced prostate cancer were treated for a minimum of 12 weeks with a daily monotherapy dose of Casodex. The doses ranged from 10 to 200 mg. Objective assessments of efficacy included: review of measurable metastases, prostate dimension, prostatic acid phosphatase and prostate-specific antigen (PSA) levels. Subjective assessments of efficacy included review of urological symptoms, performance status, bone scan and analgesic requirement. Pharmacokinetic samples were taken at various time points up to 3 months, and assayed using an achiral HPLC method.
Clear objective responses were observed, particularly at doses of 50 mg and above. Specifically, the median percentage decrease in PSA at 50 mg was 90.0%, and at 100 and 200 mg it was 93.4 and 94.8%, respectively. Up to 53% of symptomatic patients demonstrated a subjective response at 3 months. Casodex was well tolerated at all doses with no effect on haematological or cardiovascular parameters and no effect on renal function. The expected pharmacological effects of potent antiandrogen therapy, such as breast tenderness (58%), gynaecomastia (48%), and hot flushes (17%), were reported, but these incidences reflected the direct eliciting of these events. The intrinsic efficacy of Casodex was demonstrated despite increases of 60% in testosterone levels. However, this increase reached a plateau after 4-12 weeks of therapy, but the majority of values remained within the normal range. Casodex has a half-life of approximately 1 week, enabling once-daily dosing with no effect of age or renal impairment on its pharmacokinetics.
Casodex has a favourable side effect profile compared with the known safety profiles of other antiandrogens and has demonstrated intrinsic efficacy. Casodex warrants further investigation as a monotherapy for the management of advanced prostate cancer.
Prostate cancer eventually recurs during androgen deprivation therapy despite castrate levels of serum androgens. Expression of androgen receptor and androgen receptor-regulated proteins suggests androgen receptor activation in recurrent prostate cancer. Many groups have pursued mechanisms of ligand-independent androgen receptor activation but we found high levels of testicular androgens in recurrent prostate cancer tissue using RIA.
Prostate specimens from 36 men were procured preserving blood flow to prevent ischemia and cyropreserved immediately. Recurrent prostate cancer specimens from 18 men whose cancer recurred locally during androgen deprivation therapy and androgen-stimulated benign prostate specimens from 18 men receiving no hormonal treatments were studied. Tissue levels of testosterone and dihydrotestosterone were measured in each specimen using liquid chromatography/electrospray tandem mass spectrometry. Testosterone and dihydrotestosterone levels were compared with clinical variables and treatment received.
Testosterone levels were similar in recurrent prostate cancer (3.75 pmol/g tissue) and androgen-stimulated benign prostate (2.75 pmol/g tissue, Wilcoxon two-sided, P=0.30). Dihydrotestosterone levels decreased 91% in recurrent prostate cancer (1.25 pmol/g tissue) compared with androgen-stimulated benign prostate (13.7 pmol/g tissue; Wilcoxon two-sided, P < 0.0001) although dihydrotestosterone levels in most specimens of recurrent prostate cancer were sufficient for androgen receptor activation. Testosterone or dihydrotestosterone levels were not related to metastatic status, antiandrogen treatment, or survival (Wilcoxon rank sum, all P > 0.2).
Recurrent prostate cancer may develop the capacity to biosynthesize testicular androgens from adrenal androgens or cholesterol. This surprising finding suggests intracrine production of dihydrotestosterone and should be exploited for novel treatment of recurrent prostate cancer.
Androgen receptor (AR) plays a central role in prostate cancer, and most patients respond to androgen deprivation therapies, but they invariably relapse with a more aggressive prostate cancer that has been termed hormone refractory or androgen independent. To identify proteins that mediate this tumor progression, gene expression in 33 androgen-independent prostate cancer bone marrow metastases versus 22 laser capture-microdissected primary prostate cancers was compared using Affymetrix oligonucleotide microarrays. Multiple genes associated with aggressive behavior were increased in the androgen-independent metastatic tumors (MMP9, CKS2, LRRC15, WNT5A, EZH2, E2F3, SDC1, SKP2, and BIRC5), whereas a candidate tumor suppressor gene (KLF6) was decreased. Consistent with castrate androgen levels, androgen-regulated genes were reduced 2- to 3-fold in the androgen-independent tumors. Nonetheless, they were still major transcripts in these tumors, indicating that there was partial reactivation of AR transcriptional activity. This was associated with increased expression of AR (5.8-fold) and multiple genes mediating androgen metabolism (HSD3B2, AKR1C3, SRD5A1, AKR1C2, AKR1C1, and UGT2B15). The increase in aldo-keto reductase family 1, member C3 (AKR1C3), the prostatic enzyme that reduces adrenal androstenedione to testosterone, was confirmed by real-time reverse transcription-PCR and immunohistochemistry. These results indicate that enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets.
Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer
- M Stanbrough
- Bubley
- Ross K Gj
Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 2006;66:2815–25.
ENZA) monotherapy in hormone naive prostate cancer (HNPC): complete analysis of a phase 2 study [abstract 2852]. Presented at: European Cancer Congress 2013
- M Smith
- Rathenborg M P Borre
Smith M, Borre M, Rathenborg P, et al. Enzalutamide (ENZA) monotherapy in hormone naive prostate cancer (HNPC): complete analysis of a phase 2 study [abstract 2852]. Presented at: European Cancer Congress 2013; September 27–October 1, 2013; Amster-dam, The Netherlands.
The effects of enzalutamide (ENZA) in combination with abiraterone acetate (AA) in patients with bone metastatic castration resistant prostate cancer (mCRPC) [abstract 285]. Presented at: European Cancer Congress 2013
- Titus E M Efstathiou
- Wen
- As
Efstathiou E, Titus M, Wen AS, et al. The effects of enzalutamide (ENZA) in combination with abiraterone acetate (AA) in patients with bone metastatic castration resistant prostate cancer (mCRPC) [abstract 285]. Presented at: European Cancer Congress 2013; September 27–October 1, 2013; Amsterdam, The Netherlands.
ENZA) monotherapy in hormone naive prostate cancer (HNPC): complete analysis of a phase 2 study
- M Smith
- M Borre
- P Rathenborg
Smith M, Borre M, Rathenborg P, et al. Enzalutamide (ENZA)
monotherapy in hormone naive prostate cancer (HNPC): complete
analysis of a phase 2 study [abstract 2852]. Presented at: European
Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands.