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Publications (131)
Olaparib is a pioneering PARP inhibitor (PARPi) approved for treating castration-resistant prostate cancer (CRPC) tumors harboring DNA repair defects, but clinical resistance has been documented. To study acquired resistance, we developed Olaparib-resistant (OlapR) cell lines through chronic Olaparib treatment of LNCaP and C4-2B cell lines. Here, w...
169
Background: AR/AR-variants and AKR1C3 play critical roles in prostate cancer progression and driving resistance to antiandrogens, and are attractive targets for therapeutic intervention for advanced prostate cancer. However, there are currently no clinically available therapies that simultaneously target both AR/AR variants and AKR1C3. We have...
Simple Summary
Castration-resistant prostate cancer (CRPC) treatments include next-generation anti-androgen therapies (NGATs), taxane therapy, and PARP inhibitors (PARPi). However, resistance often occurs across and within therapeutic classes, which can complicate sequential treatment options. We developed acquired resistant models to study therape...
INTRODUCTION AND OBJECTIVES Androgen receptor (AR) blockade using antiandrogens is a mainstay for the treatment of castration-resistant prostate cancer (CRPC). However, resistance to antiandrogens occurs unavoidably due to the escaping mechanisms of tumor cells that are not completely understood. Upregulation of non-canonical Wnt ligand Wnt5a is id...
Introduction and Objectives: Androgen receptor (AR) blockade using antiandrogens is a mainstay for the treatment of castration-resistant prostate cancer (CRPC). However, resistance to antiandrogens occurs unavoidably due to the escaping mechanisms of tumor cells that are not completely understood. Upregulation of non-canonical Wnt ligand Wnt5a is i...
Background: Castration-resistant prostate cancer (CRPC) is an incurable disease and a leading cause of cancer death in men worldwide. Olaparib (Lynparza) was among the first PARP inhibitors (PARPi) approved for the treatment of CRPC tumors harboring DNA repair defects. However, clinical resistance to PARPi’s has been documented. The mechanisms unde...
Resistance to androgen receptor (AR) targeted therapies remains as the main reason for most prostate cancer related deaths. Lineage plasticity resulting in altered, treatment insensitive prostate tumor cell phenotypes such neuroendocrine differentiated prostate cancer is a common manifestation within resistant tumors upon AR-targeted therapies. The...
Background
Treatment-emergent neuroendocrine prostate cancer (NEPC) after androgen receptor (AR) targeted therapies is an aggressive variant of prostate cancer with an unfavorable prognosis. The underlying mechanisms for early neuroendocrine differentiation are poorly defined and diagnostic and prognostic biomarkers are needed.
Methods
We performe...
The next-generation antiandrogen drugs such as enzalutamide and abiraterone extend survival times and improve quality of life in patients with advanced prostate cancer. However, resistance to both drugs occurs frequently through mechanisms which are incompletely understood. Wnt signaling, particularly through Wnt5a, plays vital roles in promoting p...
Background: Inhibition of poly (ADP-ribose) polymerase (PARP) is an exciting treatment strategy recently approved for prostate cancer patients with homologous recombination repair defects. Despite this advance in the field, it remains unclear how PARP inhibitor (PARPi) sensitive cells respond to treatment. We previously demonstrated that treatment...
PARP inhibition represents the dawn of precision medicine for treating prostate cancer. Despite this advance, questions remain regarding the use of PARP inhibitors (PARPi's) for the treatment of this disease, including 1) how specifically do PARPi sensitive tumor cells respond to treatment, and 2) how does PARPi resistance develop? To address these...
Targeting androgen signaling with the second-generation anti-androgen drugs, such as enzalutamide (Enza), abiraterone (Abi), apalutamide (Apal), and darolutamide (Daro), is the mainstay for the treatment of castration-resistant prostate cancer (CRPC). While these treatments are effective initially, resistance occurs frequently. Continued expression...
Docetaxel and cabazitaxel based taxane chemotherapy are critical components in the management of advanced prostate cancer. However, their efficacy is hindered due to de novo presentation with or the development of resistance. Characterizing models of taxane resistant prostate cancer will lead to creation of strategies to overcome insensitivity. We'...
Purpose:
Most prostate cancer patients receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active dehydroepiandrosterone (DHEA) remain in the high range despite anti-androgen treatment. The conversion of DHEAS into DHEA by steroid sulfata...
p>Prostate cancer is the most common cancer in men and it is estimated that 32,000 men in the US alone will die of this cancer in 2019. Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer therapy. However, most of the patients will progress to castration resistance prostate cancer (CRPC) after several years of treatment. The...
The next generation anti-androgen drugs, XTANDI® (Enzalutamide), ZYTIGA® (Abiraterone acetate), ERLEADA™ (Apalutamide) and NUBEQA (Darolutamide) extend survival times and improve quality of life in advanced prostate cancer patients. Despite these advances, resistance occurs frequently and there is currently no definitive cure for Castration-Resista...
Background:
De-regulation of Wnt signaling pathways has been shown to be associated with progression of castration-resistant prostate cancer and more recently, studies indicate that both canonical and non-canonical Wnt pathways may mediate resistance to anti-androgen therapies such as enzalutamide. However, the mechanisms by which Wnt signaling is...
The mechanisms resulting in resistance to next generation anti-androgens in castration resistant prostate cancer are imcompletely understood. Numerous studies have determined that constitutively active androgen receptor (AR) signaling or full length AR bypass mechanisms may contribute to the resistance. Previous studies established that AKR1C3 and...
Castration-resistant prostate cancer remains as an incurable disease. Exploiting DNA damage repair defects via inhibition of poly (ADP-ribose)polymerase (PARP)is becoming an attractive therapeutic option. The TOPARP-A clinical trial demonstrated that the PARP inhibitor olaparib may be an effective strategy for treating prostate cancer. However, sev...
While small nucleolar RNAs (snoRNAs) have long been thought of as housekeeping genes, emerging evidence now suggests that snoRNAs are involved in more than previously thought and also in the development of disease. In cancer, it is understood that snoRNA expression and function can be altered, but little is known regarding the role of snoRNAs in th...
INTRODUCTION AND OBJECTIVES: Proteostasis is a complementary process by which cells control the protein biosynthesis, folding, trafficking and degradation. Evidence suggests that proteomic instability, such as protein misfolding and aggregation plays pivotal roles in cancer cell survival and progression. AR-V7 lacking the ligand binding domain conf...
While small nucleolar RNAs (snoRNAs) have long been thought of as housekeeping genes, emerging evidence now suggests that snoRNAs are involved in more than previously thought and also in the development of disease. In cancer, it is understood that snoRNA expression and function can be altered, but little is known regarding the role of snoRNAs in th...
Resistance to anti-androgens, such as enzalutamide (Enza) or abiraterone (Abi), develops within 24 months of initial exposure in most prostate cancer (PCa) patients. Commonly, dysregulated androgen signaling is a key feature of resistant disease. Previous studies demonstrate that androgen synthesis is upregulated in Enza and Abi resistance. HSD3B1...
Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR v...
Current treatments for castration resistant prostate cancer (CRPC) largely fall into two major classes; AR-targeted therapies such as the next-generation anti-androgen therapies (NGATs), enzalutamide and abiraterone, and taxanes such as docetaxel and cabazitaxel. Despite improvements in outcomes, patients still succumb to the disease due to the dev...
Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next generatio...
in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different t...
Introduction: Docetaxel (DTX) is one of the primary drugs used for treating castration resistant prostate cancer (CRPC). Unfortunately, over time patients invariably develop resistance to DTX therapy and their disease will continue to progress. The mechanisms by which resistance develops are still incompletely understood. This study seeks to determ...
Background:
Docetaxel is one of the primary drugs used for treating castration resistant prostate cancer (CRPC). Unfortunately, over time patients invariably develop resistance to docetaxel therapy and their disease will continue to progress. The mechanisms by which resistance develops are still incompletely understood. This study seeks to determi...
Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants...
161Background: Enzalutamide (Enza) improves the treatment of metastatic castration-resistant PCa (mCRPC). Acquired resistance is the most common cause of treatment failure. Our objective was to determine mechanisms of resistance to Enza and develop novel therapy to overcome resistance. Methods: Enza-resistant PCa cells were established through cont...
Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a crit...
Background:
Prostate cancer (PCa) is androgen-dependent initially and progresses to a castration-resistant state after androgen deprivation therapy. Treatment options for castration-resistant PCa include the potent second-generation anti-androgen enzalutamide or CYP17A1 inhibitor abiraterone. Recent clinical observations point to the development o...
Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2B-TaxR cells. . In this study, we examined if anti-androgens, such as bicalutamide and enzalutamide, could inhibit ABCB1 activity and overcome resistance to docetaxel.
ABCB1 efflux activity was determined using a rhodamine efflux assay. ABCB1 AT...
Purpose:
It is known that over expression of IL6 in prostate cancer cells confer enzalutamide resistance and that this may occur through constitutive Stat3 activation. Additionally, recent pre-clinical studies suggested enzalutamide might have the potential adverse effect of inducing metastasis of prostate cancer cells via Stat3 activation. This s...
Castration resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling. Alternative splicing of the AR to generate constitutively active, ligand-independent variants is one of the principal mechanisms that promote the development of resistance to next-generation anti-androgens such as enzalutamide. Here, we demonstrate th...
The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide resistant prostate can...
Considerable evidence from both clinical and experimental studies suggests that androgen receptor variants, particularly androgen receptor variant 7 (AR-V7), are critical in the induction of resistance to enzalutamide and abiraterone. In this study, we investigated the role of AR-V7 in the cross-resistance of enzalutamide and abiraterone and examin...
BACKGROUND
Paracrine interleukin-6 (IL-6) can mediate neuroendocrine (NE) features, including the acquisition of a neurite-like phenotype and growth arrest in prostate cancer cells. However, little is known about the mechanisms underlying neuroendocrine differentiation induced by IL-6.METHODS
Immunoblotting was performed to determine the status of...
Enzalutamide, a second-generation antiandrogen, was recently approved for the treatment of castration-resistant prostate cancer (CRPC) in patients who no longer respond to docetaxel. Despite these advances that provide temporary respite, resistance to enzalutamide occurs frequently.This study was designed to identify inhibitors of AR variants and t...
Use of enzalutamide has improved the treatment of advanced prostate cancer. However, resistance to enzalutamide can develop frequently in initial responders. This study aimed to test whether overexpression of IL-6 and constitutive activation of Stat3 in prostate cancer cells increase resistance to enzalutamide.
Sensitivity of prostate cancer cells...
Cancer cells reprogram their metabolism pathways to facilitate fast proliferation. Previous studies have shown that overexpression of NF-kappa B2/p52 (p52) in prostate cancer cells promotes cell growth and leads to castration resistance through aberrant activation of androgen receptor. In addition, these cells become resistant to enzalutamide. In t...
Introduction and objective: Inflammation plays a key role in the etiology of carcinoma of colon, cervix or liver, but PCa, in which inflammation has not been deemed to play a causative role, also display a pro-inflammatory gene profile. NF-κB is central to the induction of inflammation and the classical and alternative NF-κB activation pathways hav...
Treatment of primary prostate cancer (CaP) is the withdrawal of androgens. However, CaP eventually progresses to grow in a castration-resistant state due to aberrant activation of androgen receptor (AR). Understanding the mechanisms leading to the aberrant activation of AR is critical to develop effective therapy. We have previously identified Rho...
Docetaxel is the first-line standard treatment for castration resistant prostate cancer (CRPC). However, relapse eventually occurs due to the development of resistance to docetaxel. In order to unravel the mechanism of acquired docetaxel resistance, we established docetaxel-resistant prostate cancer cells, TaxR, from castration resistant C4-2B pros...
Prostate cancer (CaP) progresses to a castration-resistant state assisted by multifold molecular changes, most of which involve activation of the androgen receptor (AR). Having previously demonstrated the importance of the Lin28/let-7/Myc axis in CaP, we tested the hypothesis that Lin28 is overexpressed in CaP and that it activates AR and promotes...
Resistance of prostate cancer (CaP) cells to the next generation anti-androgen, Enzalutamide, may be mediated by a multitude of survival signaling pathways. In this study we tested whether increased expression of NF-κB2/p52 induces CaP cell resistance to Enzalutamide and whether this response is mediated by aberrant androgen receptor (AR) activatio...
Introduction and Objective: Despite initial response of prostate cancer (CaP) to androgen deprivation, clinical observations suggest that castration-resistant prostate cancer (CRPC) develops resistance to the recently approved anti-androgen, enzalutamide. There is an urgent need to identify pathways that perpetuate disease progression during AR blo...
Docetaxel is the first line treatment for castration resistant prostate cancer (CRPC). However, docetaxel resistance rapidly develops. Identifying the critical mechanisms giving rise to docetaxel resistance is the major challenge in advanced prostate cancer.
The effects of docetaxel on human DU145, PC3, LNCaP, and C4-2 prostate cancer cells were ex...
Prostate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa.
Levels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ...
Treatment for primary prostate cancer (CaP) is the withdrawal of androgens. However, CaP eventually progresses to grow in a castration-resistant state. The mechanisms involved in the development and progression of castration-resistant prostate cancer (CRPC) remain unknown. We have previously generated LNCaP-IL6+ cells by treating LNCaP cells chroni...
Signal transducer and activator of transcription 3 (Stat3) is an oncogenic transcriptional factor that plays a critical role in carcinogenesis and cancer progression and is a potential therapeutic target. Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified previously as a novel inhibitor of surviv...
Castration-resistant prostate cancer continues to rely on androgen receptor (AR) expression. AR plays a central role in the
development of prostate cancer and progression to castration resistance during and after androgen deprivation therapy. Here,
we identified miR-let-7c as a key regulator of expression of AR. miR-let-7c suppresses AR expression...
Introduction: MicroRNAs (miRNA) are small ∼22 nt non-coding RNAs that regulate gene expression by binding to and inducing degradation of target mRNAs. Deregulated expression of several miRNAs has been found in prostate cancer cells. Let-7 is an evolutionarily conserved family of miRNAs that have been shown to regulate expression of several oncogene...
INTRODUCTION AND OBJECTIVES: Elevated interleukin-6 (IL-6), a major mediator of the inflammatory response, has been implicated in androgen receptor (AR) activation, cellular growth and differentiation, plays important roles in the development and progression of prostate cancer, and is a potential target in cancer therapy.
METHODS: In an attempt to...
Androgen receptor (AR) signaling not only plays a pivotal role in the development of androgen-dependent prostate cancer but is also important in the growth and survival of castration-resistant prostate cancer (CRPC). The first line of treatment of androgen-dependent prostate cancer is the use of androgen deprivation therapy. However, most patients...
INTRODUCTION: Castration-resistant progression of prostate cancer occurs in >80% of patients after failure of hormonal therapy but the underlying mechanisms are incompletely understood. Emerging evidence implies that ligand-independent activation of the androgen receptor (AR) is of critical importance during this process. Our previous studies show...
Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC
INTRODUCTION AND OBJECTIVES: The standard systemic treatment for prostate cancer patients is androgen deprivation therapy. Although serum testosterone concentrations were significantly reduced after androgen deprivation therapy, levels of intraprostatic androgens are rep...
Background: Prostate cancer is a frequently occurring disease and is the second leading cause of cancer related deaths of men in the United States. Current treatments have proved inadequate in curing or controlling prostate cancer and a search for agents for the management of this disease is urgently needed. Survivin plays an important role in both...
Elevated interleukin-6 (IL-6), a major mediator of the inflammatory response, has been implicated in androgen receptor (AR) activation, cellular growth and differentiation, plays important roles in the development and progression of prostate cancer, and is a potential target in cancer therapy. Through drug screening using human prostate cancer cell...
Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC
Introduction: The high prevalence of osteoblastic bone metastases in prostate cancer likely involves the production of osteoblast-stimulating factors by prostate cancer cells. The identity of the factors responsible for the homing of circulating prostate cancer cells to...
