ArticleLiterature Review

Mechanisms of Disease: Oncogene addiction - A rationale for molecular targeting in cancer therapy

September 2006
Nature Clinical Practice Oncology 3(8):448-57

September 2006
3(8):448-57

Source
PubMed

Authors:

There has been considerable progress in the systemic treatment of cancer because of the rapid development and clinical application of molecular targeted agents. Although patients with a particular type and stage of cancer are often treated as a single group, more-specific therapy is being considered, as subsets of these patients who are more likely to benefit from treatment with particular agents are being identified. We previously introduced the concept of 'oncogene addiction' to explain how some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities are dependent on or 'addicted' to one or a few genes for both maintenance of the malignant phenotype and cell survival. Thus, reversal of only one or a few of these abnormalities can inhibit cancer cell growth and in some cases translate to improved survival rates. This review summarizes current experimental and clinical evidence for the concept of oncogene addiction and describes molecular mechanisms that may explain this phenomenon. In addition, we discuss how high-throughput screening methods, including gene-expression profiling and proteomics, and emerging methods for analyzing complex cellular networks can be used to identify the state of oncogene addiction, i.e. the 'Achilles' heel,' in specific cancers. Finally, we discuss the use of molecular targeted agents in combination with other anticancer agents as a strategy to optimize therapy and prevent disease recurrence.

Cellular Response to an Act of Surviving Drives Tumor Evolution and Tumor Heterogeneity

Preprint

Full-text available

Nov 2023

Yuntian Zhang

Tumor heterogeneity is a major obstacle to achieving consistent outcomes in cancer therapy. We offer a novel perspective on tumor heterogeneity, informed by an advanced understanding of tumor evolution. We understand any cells, or any organism, will inherently respond with specific capacities when faced with adversity. Our concepts, which extend beyond canonical views, posit that tumor evolution is driven by cellular responses to survival challenges. The disease is driven by a rudimentary action taken by any organism when confronted with adversity - a cellular response to generate specific capacities to overcome the threat - the responses that utilize advantageous genetic mutations and other cellular contents to attain these capacities and further drive the disease. The disease is initiated by a cellular response to survival challenges and the ongoing development of hallmark cancer capabilities, as cells endeavor to obtain a competitive advantage, results in increased molecular disarray, observed as tumor heterogeneity. When the evolutionary drive for survival is impeded by therapeutic inhibition of critical genes, cell death occurs, a phenomenon termed oncogene addiction. Drawing from the same idea that cells responding to survival challenges, we recognize the increasing primitiveness of cancer during its progress stems from the innate cellular response to the demand for regeneration under sustained cellular damage. This necessitates a regression to a more primitive state purposed to renew progeny, unleashing a hitherto undiscerned cellular capacity. Taken together, the ideas explored herein pave the way for novel cancer therapies and the betterment of human health.

Cellular Response to an Act of Surviving Drives Tumor Evolution and Tumor Heterogeneity

Preprint

Full-text available

Oct 2023

Yuntian Zhang

Tumor heterogeneity is a major obstacle to achieving consistent outcomes in cancer therapy. Here, we present a new perspective on tumor heterogeneity. The foundation for understanding tumor heterogeneity lies in recognizing that tumor evolution is a process driven by cells responding to survival challenges, and this cellular response precipitates the development of hallmark cancer capabilities. We posit that tumor heterogeneity arises from cells’ continued development of hallmark cancer capabilities, which ultimately leads to increased molecular chaos. Therapeutic inhibition of the essential genes driving the disease can disrupt tumor evolution, leading to cell death, a phenomenon termed oncogene addiction. Drawing from the same idea that cells respond to survival challenges, we introduce the notion that the increasing primitiveness of cancer during its progress stems from the cellular response to the continuous need for regeneration due to sustained cellular damage. To expand our concept of tumor heterogeneity, we further explore redefining key genes based on heterogeneity levels, and we propose a potential treatment strategy for advanced-stage cancers based on inducing aging-related deterioration. Taken together, the notions explored herein pave the way for novel cancer therapies and the betterment of human health.

Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights

Article

Full-text available

Apr 2022

In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds 9h, 11d, 11e and 13c showed potent inhibitory activity (IC50 of 40.91, 41.70, 46.88, and 52.63 nM, respectively) compared to staurosporine (IC50 of 56.76 nM). Moreover, benzofurans 9e, 9h, 11d, and 13b showed promising antiproliferative activities towards different cancer cell lines, and non-significant cytotoxicity on normal lung fibroblasts MRC-5 cell line. Furthermore, a cell cycle analysis as well as Annexin V-FITC apoptosis assay on Panc-1 cell line were performed. Molecular docking simulations were performed to explore the ability of target benzofurans to adopt the common binding pattern of CDK2 type II inhibitors.

INSIGHT INTO THE MOLECULAR TARGETS AND DRUG DEVELOPMENT AGAINST LUNG CANCER

Chapter

Mar 2024

Book series on Medical Science gives the opportunity to students and doctors from all over the world to publish their research work in a set of Preclinical sciences, Internal medicine, Surgery and Public Health. This book series aim to inspire innovation and promote academic quality through outstanding publications of scientists and doctors. It also provides a premier interdisciplinary platform for researchers, practitioners, and educators to publish the most recent innovations, trends, and concerns as well as practical challenges encountered and solutions adopted in the fields of Medical Science. It also provides a remarkable opportunity for the academic, research and doctors communities to address new challenges and share solutions.

Canonical and Noncanonical Functions of the BH3 Domain Protein Bid in Apoptosis, Oncogenesis, Cancer Therapeutics, and Aging

Article

Full-text available

Jun 2024

Simple Summary Cancer remains a debilitating disease and a worldwide health burden, and their treatment has been a forefront interest for researchers and clinicians for centuries. The search for novel approaches to selectively target certain proteins in just cancer cells, while sparing normal, healthy cells, has been the holy grail to limit side effects of treatments. This review aims to assess the potential of tBid, a pro-apoptotic mitochondrial protein found in normal and healthy cells, as a target for treating cancers. Cancer cells with tBid accumulation at mitochondria are “primed” for apoptosis, and, surprisingly, may be resistant to apoptosis owing to the association of tBid with antiapoptotic proteins. These cancer cells are more vulnerable to drugs that target these associations, with the possibility of limiting the use of chemo- or other cancer therapies. Abstract Effective cancer therapy with limited adverse effects is a major challenge in the medical field. This is especially complicated by the development of acquired chemoresistance. Understanding the mechanisms that underlie these processes remains a major effort in cancer research. In this review, we focus on the dual role that Bid protein plays in apoptotic cell death via the mitochondrial pathway, in oncogenesis and in cancer therapeutics. The BH3 domain in Bid and the anti-apoptotic mitochondrial proteins (Bcl-2, Bcl-XL, mitochondrial ATR) it associates with at the outer mitochondrial membrane provides us with a viable target in cancer therapy. We will discuss the roles of Bid, mitochondrial ATR, and other anti-apoptotic proteins in intrinsic apoptosis, exploring how their interaction sustains cellular viability despite the initiation of upstream death signals. The unexpected upregulation of this Bid protein in cancer cells can also be instrumental in explaining the mechanisms behind acquired chemoresistance. The stable protein associations at the mitochondria between tBid and anti-apoptotic mitochondrial ATR play a crucial role in maintaining the viability of cancer cells, suggesting a novel mechanism to induce cancer cell apoptosis by freeing tBid from the ATR associations at mitochondria.

Prognostic and predictive biomarkers with therapeutic targets in nonsmall-cell lung cancer: A 2023 update on current development, evidence, and recommendation

Article

Full-text available

Apr 2024
J Oncol Pharm Pract

Background Since the publication of the original work in 2014, significant progress has been made in the characterization of genomic alterations that drive oncogenic addiction of nonsmall cell lung cancer (NSCLC) and how the immune system can leverage non-oncogenic pathways to modulate therapeutic outcomes. This update evaluates and validates the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in NSCLC. Data sources We performed a literature search from January 2015 to October 2023 using the keywords non-small cell lung cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, circulating tumor DNA, predictive and prognostic biomarkers, and targeted therapies. Study selection and data extraction We identified, reviewed, and evaluated relevant clinical trials, meta-analyses, seminal articles, and published clinical practice guidelines in the English language. Data synthesis Regulatory-approved targeted therapies include those somatic gene alterations of EGFR (“classic” mutations, exon 20 insertion, and rare EGFR mutations), ALK, ROS1, BRAF V600, RET, MET, NTRK, HER2, and KRAS G12C. Data for immunotherapy and circulating tumor DNA in next-generation sequencing are considered emerging, whereas the predictive role for PIK3CA gene mutation is insufficient. Conclusions Advances in sequencing and other genomic technologies have led to identifying novel oncogenic drivers, novel resistance mechanisms, and co-occurring mutations that characterize NSCLC, creating further therapeutic opportunities. The benefits associated with immunotherapy in the perioperative setting hold initial promise, with their long-term results awaiting.

Effects of post-fermentation addition of green tea extract for sulfur dioxide replacement on Sauvignon Blanc wine phenolic composition, antioxidant capacity, colour, and mouthfeel attributes

Article

Full-text available

Mar 2024
FOOD CHEM

This study examines the feasibility of replacing SO2 in a New Zealand Sauvignon Blanc wine with a green tea extract. The treatments included the control with no preservatives (C), the addition of green tea extract at 0.1 and 0.2 g/L (T1 and T2), and an SO2 treatment at 50 mg/L (T3). Five monomeric phenolic compounds were detected in the green tea extract used for the experiment, and their concentrations ranged in the order (−)-epigallocatechin gallate > (−)-epigallocatechin > (−)-epicatechin > (−)-epicatechin gallate > gallic acid. At the studied addition rates, these green tea-derived phenolic compounds contributed to ~70% of the antioxidant capacity (ABTS), ~71% of the total phenolic index (TPI), and ~ 84% of tannin concentration (MCPT) of the extract dissolved in a model wine solution. Among wine treatments, T1 and T2 significantly increased the wine's colour absorbance at 420 nm, MCPT, gallic acid and total monomeric phenolic content. TPI and ABTS were significantly higher in wines with preservatives (i.e., T2 > T1 ≅ T3 > C, p < 0.05). These variations were observed both two weeks after the treatments and again after five months of wine aging. Additionally, an accelerated browning test and a quantitative sensory analysis of wine colour and mouthfeel attributes were performed after 5 months of wine aging. When exposed to excessive oxygen and high temperature (50 °C), T1 and T2 exhibited ~29% and 24% higher browning capacity than the control, whereas T3 reduced the wine's browning capacity by ~20%. Nonetheless, the results from sensory analysis did not show significant variations between the treatments. Thus, using green tea extract to replace at wine bottling appears to be a viable option, without inducing a negative impact on the perceptible colour and mouthfeel attributes of Sauvignon Blanc wine.

Molecular docking and pharmacophore analysis of trisindoline 1 against human topoisomerase II and human derived growth factor

Conference Paper

Full-text available

Mar 2024

Liver cancer is currently a leading cause of death worldwide and its incidence is increasing. As a result, there has been an increase in the development of computational drug design strategies utilizing molecules for anti-cancer candidates over the last decade. DNA topoisomerase II (topo II) enzymes play a crucial role in regulating essential cellular processes by altering the topology of chromosomal DNA. The PDGF receptor is a promising anti-cancer target and is used as a prognostic marker for liver cancer due to its ability to interact with topo II enzymes. Trisindoline 5’-nitro-[3,3 ’: 3’, 3”-terindoline]-2’-one is a cytotoxic indole trimer alkaloid compound that induces apoptosis in the HepG2 cell line. This study investigated the potential of Trisindoline 1 as an alternative drug for liver cancer by conducting molecular docking against topo II and PDGF. The binding energy value of Trisindoline 1 against human topo II was -10.1 Kcal/mol, which was higher than the binding energy value of doxorubicin (-9.2 Kcal/mol). Furthermore, pharmacophore analysis of Trisindoline 1 indicated that it possesses drug-like properties and lower toxicity than doxorubicin. Trisindoline 1 has the potential to inhibit PDGF and human topo II enzymes in liver cancer through the apoptotic pathway.

The Targeted Degradation of BRAF V600E Reveals the Mechanisms of Resistance to BRAF-Targeted Treatments in Colorectal Cancer Cells

Article

Full-text available

Dec 2023

Simple Summary The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers. This study uses a proteolysis targeting chimera (PROTAC) to probe the role of BRAF V600E in colorectal and triple-negative breast cancer cells. The study reveals a diverse set of biochemical and proliferative responses to BRAF V600E degradation: some cancer cells are killed by BRAF degradation, while others utilize additional oncogenic drivers, such as Src kinase phosphatidylinositol 3-kinase, to resist the effect of BRAF degradation. These responses provide a mechanistic explanation for the efficacy of BRAF-targeted therapy for some cancers and the intrinsic resistance in others. Abstract The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers harboring the BRAF mutation. In this study, we evaluate the effectiveness of a proteolysis targeting chimera (PROTAC), SJF-0628, in directing the degradation of mutated BRAF across a diverse panel of cancer cells and determine how these cells respond to the degradation. SJF-0628 treatment results in the degradation of BRAF V600E and a decrease in Mek activation in all cell lines tested, but the effects of the treatment on cell signaling and cell proliferation are cell-line-specific. First, BRAF degradation killed DU-4475 and Colo-205 cells via apoptosis but only partially inhibited the proliferation of other cancer cell lines. Second, SJF-0628 treatment resulted in co-degradation of MEK in Colo-205 cells but did not have the same effect in other cell lines. Finally, cell lines partially inhibited by BRAF degradation also contain other oncogenic drivers, making them multi-driver cancer cells. These results demonstrate the utility of a PROTAC to direct BRAF degradation and reveal that multi-driver oncogenesis renders some colorectal cancer cells resistant to BRAF-targeted treatment.

DEVELOPMENT, CHARACTERIZATION AND EVALUATION OF ENTRECTINIB NANOSPONGES LOADED TABLETS FOR ORAL DELIVERY

Article

Full-text available

Nov 2023

Objective: As Entrectinib is a lipophilic, basic, moderately permeable molecule with strongly pH-dependent solubility with antitumor activity in advanced and metastatic solid tumors, the current study was designed to improve the oral solubility of Entrectinib through incorporation into nanosponges tablets (NSs). Methods: Box-Behnken Design was used to optimize the independent variables of β-Cyclodextrin (β-CD) NSs formation. β-CD NSs were prepared by an ultrasound-assisted method using diphenyl carbonate as cross-linking agent, which were later characterized and formulated into tablets by wet granulation method. The prepared tablets were evaluated for the physico-chemical properties and in vitro release of the drug. Results: A series of fifteen experiments were performed based on the experimental runs generated from a three-factor, three-level Box–Behnken design (BBD). The range of mean particle size was 149-294 nm, the range for encapsulation efficiency % was 65.4%-87.3%, and the value for polydispersity index was 0.437. The zeta potential for the optimized formulation was found to be 38.1 Mv. The drug and excipients were compatibles as confirmed by Fourier Transformed Infrared (FTIR) Spectroscopy and Differential Scanning Calorimetry (DSC) studies. Scanning Electron Microscopic (SEM) analysis confirmed that the Entrectinib has successfully entrapped in the core of polymer. In vitro release of the Entrectinib-loaded NSs tablets (six compositions) were compared with a marked product and satisfactory results were obtained. It was observed that rapid dissolution occurred in 0.1 N HCl for first 2 h (15.64±1.52% vs. 12.67±1.89%) and 98.94±2.43% of drug release was observed in Entrectinib loaded NSs and 91.78±1.37% in marketed product in 24 h. The prepared formulations were stable during 6 mo stability study period. Conclusion: The study results studies of Entrectinib NS tablets indicated rapid dissolution due to changed solubility properties of the drug, compared to pure drug meeting the set objective of enhanced absorption. The formulated Entrectinib-loaded NSs can be beneficial in the treatment of cancers.

The frequency of different types of squamous cell carcinoma according to their triggering factors in patients with dark complexion skin

Article

Full-text available

Oct 2023

Resistance of Lung Cancer to EGFR-Specific Kinase Inhibitors: Activation of Bypass Pathways and Endogenous Mutators

Article

Full-text available

Oct 2023

Simple Summary Genome-based cancer medicine is becoming the standard of care: the patient’s tumor DNA is first analyzed to identify driver mutations, and this permits later selection of the most effective drugs. Treatment of lung cancer offers many examples. Activating mutations in the epidermal growth factor receptor (EGFR) gene, as well as in other receptor tyrosine kinases (e.g., ALK), are considered actionable candidates, and the respective drugs, called tyrosine kinase inhibitors, are relatively effective. Unfortunately, despite initial activity, the emergence of new, on-target mutations, along with adaptive processes, preempt the anti-cancer effects and necessitate switching to next-generation drugs. This review highlights recent progress in resolving the mechanisms that underlie acquisition of resistance. Specifically, we focus on the endogenous mutators that initiate emergence of new mutations and the potential clinical benefits that may be derived from this new understanding. Abstract Epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) have changed the landscape of lung cancer therapy. For patients who are treated with the new TKIs, the current median survival exceeds 3 years, substantially better than the average 20 month survival rate only a decade ago. Unfortunately, despite initial efficacy, nearly all treated patients evolve drug resistance due to the emergence of either new mutations or rewired signaling pathways that engage other receptor tyrosine kinases (RTKs), such as MET, HER3 and AXL. Apparently, the emergence of mutations is preceded by a phase of epigenetic alterations that finely regulate the cell cycle, bias a mesenchymal phenotype and activate antioxidants. Concomitantly, cells that evade TKI-induced apoptosis (i.e., drug-tolerant persister cells) activate an intrinsic mutagenic program reminiscent of the SOS system deployed when bacteria are exposed to antibiotics. This mammalian system imbalances the purine-to-pyrimidine ratio, inhibits DNA repair and boosts expression of mutation-prone DNA polymerases. Thus, the net outcome of the SOS response is a greater probability to evolve new mutations. Deeper understanding of the persister-to-resister transformation, along with the development of next-generation TKIs, EGFR-specific proteolysis targeting chimeras (PROTACs), as well as bispecific antibodies, will permit delaying the onset of relapses and prolonging survival of patients with EGFR⁺ lung cancer.

RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy

Article

Full-text available

Sep 2023

Hae Ryung Chang

Ubiquitination is a post-translational modification (PTM) that is involved in proteolysis, protein–protein interaction, and signal transduction. Accumulation of mutations and genomic instability are characteristic of cancer cells, and dysfunction of the ubiquitin pathway can contribute to abnormal cell physiology. Because mutations can be critical for cells, DNA damage repair, cell cycle regulation, and apoptosis are pathways that are in close communication to maintain genomic integrity. Uncontrolled cell proliferation due to abnormal processes is a hallmark of cancer, and mutations, changes in expression levels, and other alterations of ubiquitination factors are often involved. Here, three E3 ubiquitin ligases will be reviewed in detail. RNF126, RNF168 and CUL1 are involved in DNA damage response (DDR), DNA double-strand break (DSB) repair, cell cycle regulation, and ultimately, cancer cell proliferation control. Their involvement in multiple cellular pathways makes them an attractive candidate for cancer-targeting therapy. Functional studies of these E3 ligases have increased over the years, and their significance in cancer is well reported. There are continuous efforts to develop drugs targeting the ubiquitin pathway for anticancer therapy, which opens up the possibility for these E3 ligases to be evaluated for their potential as a target protein for anticancer therapy.

Targeting cyclin D1 as a therapeutic approach for papillary thyroid carcinoma

Article

Full-text available

Jun 2023

Cyclin D1 functions as a mitogenic sensor that specifically binds to CDK4/6, thereby integrating external mitogenic inputs and cell cycle progression. Cyclin D1 interacts with transcription factors and regulates various important cellular processes, including differentiation, proliferation, apoptosis, and DNA repair. Therefore, its dysregulation contributes to carcinogenesis. Cyclin D1 is highly expressed in papillary thyroid carcinoma (PTC). However, the particular cellular mechanisms through which abnormal cyclin D1 expression causes PTC are poorly understood. Unveiling the regulatory mechanisms of cyclin D1 and its function in PTC may help determine clinically effective strategies, and open up better opportunities for further research, leading to the development of novel PTC regimens that are clinically effective. This review explores the mechanisms underlying cyclin D1 overexpression in PTC. Furthermore, we discuss the role of cyclin D1 in PTC tumorigenesis via its interactions with other regulatory elements. Finally, recent progress in the development of therapeutic options targeting cyclin D1 in PTC is examined and summarized.

Molecular Basis of Sex Differences in Cancer: Perspective from Asia

Article

Full-text available

Jun 2023

Cancer is a leading cause of mortality and morbidity globally. Sex differences in cancer are evident in death rates and treatment responses in several cancers. Asian patients have unique cancer epidemiology influenced by their genetic ancestry and sociocultural factors in the region. In this review, we show molecular associations that potentially mediate sex disparities observed in cancer in the Asian population. Differences in sex characteristics are evident at the cytogenetic, genetic, and epigenetic levels mediating processes that include cell cycle, oncogenesis, and metastasis. Larger clinical and in vitro studies that explore mechanisms can confirm the associations of these molecular markers. In-depth studies of these markers can reveal their importance as diagnostics, prognostics, and therapeutic efficacy markers. Sex differences should be considered in designing novel cancer therapeutics in this era of precision medicine.

Targeted therapy for lung cancer: Beyond EGFR and ALK

Article

Full-text available

Apr 2023
CANCER-AM CANCER SOC

Precision oncology comprises the set of strategies that aim to design the best cancer treatment based on tumor biology. A recognized subset of patients with non‐small cell lung cancer (NSCLC) harbor actionable genomic aberrations that can benefit from targeted therapy. In lung cancer, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are well characterized oncogenic drivers for which the therapeutic use of tyrosine kinase inhibitors has demonstrated improved outcomes compared with chemotherapy. Other druggable targets are also well characterized, and effective inhibitors have been developed and commercialized, leading to a paradigm shift in NSCLC treatment. Here, the authors provide a review of the oncogenic role of the most relevant molecular alterations in NSCLC and emerging treatments in this setting beyond EGFR‐driven and ALK‐driven diseases.

Formulation Development, Optimization, and Characterization of Entrectinib-Loaded Supersaturable Self-Nanoemulsifying Drug Delivery Systems

Article

Full-text available

Apr 2023

Entrectinib is a novel potent anticancer drug with poor aqueous solubility. A supersaturable self-nanoemulsifying drug delivery system of entrectinib is developed using a super saturation promoter. The components of the isotropic mixture of SNEDDS were selected based on solubility and emulsification study. The optimum composition was identified using phase diagrams and further optimized by mixture design. The supersaturated SNEDDS was prepared using HPMC K4M as precipitation inhibitor. The droplet of sSNEDDS ranges from 118.42 ± 1.26 to 128.34 ± 0.63 nm with PDI values range from 0.112 to 0.204, which is significantly smaller than that observed with plain SNEDDS. The percent transmittance of the diluted formulation was found to be 98.78 ± 0.74. The viscosity was found to be 528 ± 32 centipoises indicating the good flow ability. FTIR and DSC studies indicated the amorphization of the drug. The dissolution profile of sSNEDDS indicated the faster release of drug compared to both pure drug suspension and SNEDDS formulation. The drug release rate is directly proportional to the concentration of the drug. The drug release from the insoluble matrix is a square root of time-dependent Fickian diffusion process. The formulation was found to be stable and transparent at all pH values and the percent transmittance was more than 95%. No significant difference was observed with all the samples exposed at different storage conditions. This study demonstrated the feasibility of stabilizing and improving the in vitro performance of SNEDDS by incorporating HPMC K4M as precipitation inhibitor. Graphical abstract

Exploring the adsorption performance of doped graphene quantum dots as anticancer drug carriers for cisplatin by DFT, PCM, and COSMO approaches

Article

Full-text available

Mar 2023
STRUCT CHEM

Due to less sensitivity of graphene towards the cisplatin (CPT), the graphene is modified by doping systematically boron atoms (B/Gra), nitrogen atoms (N/Gra), and hexagonal boron nitride (BN/Gra) to form hetero-quantum dots (QDs). In our DFT investigations, the CPT drug adsorbs on the surface of modified QDs within favorable range of adsorption energy. Among them, B/Gra QD shows high adsorption behavior with CPT at about −1.44 eV and −0.6 eV energies in gas and water solvent phases. On the other hand, BN/Gra and N/Gra hetero-QDs interact with CPT at about −0.88 eV and −1.03 eV adsorption energies respectively. During interaction of CPT with B/Gra, CPT loses 0.215 e and 0.129 e charge to the B/Gra in gas and solvent phases. About 26.4% and 14% reductions of E g have been occurred after the interaction of CPT with B/ Gra. Furthermore quantum molecular descriptors also suggest the high sensitivity of the B/Gra QDs with the CPT. Therefore, B/Gra QD can be used as drug carrier for CPT.

Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors

Article

Full-text available

Feb 2023

Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC. Methods: We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin-like growth factor-binding protein-1 (IGFBP-1) levels of 31 lenvatinib-treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain- and loss-of-function experiments were performed. Results: In the patient cohort, IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling. IGFBP-1 stimulated angiogenesis through activation of the integrin α5β1-focal adhesion kinase pathway. Consequently, loss of IGFBP-1 and integrin α5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment. Conclusions: Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP-1, which promoted angiogenesis through activating the IGFBP-1-integrin α5β1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.

Kanserde Hedefe Yönelik Tedavi: PI3K/Akt/mTOR İnhibitörleri

Article

Full-text available

Mar 2022

Serhan Kupeli

Kanserler genel olarak çoklu genetik ve epigenetik anormallikler içermekte fakat birkaç anahtar gen sayesinde malign fenotip ve hücresel sağkalımın devamlılığı sağlanmaktadır. PI3K/Akt/mTOR yolağı önemli birçok fizyolojik olaylarda rol alan merkezi bir sinyal akım sistemidir. PI3K/Akt/mTOR yolağı birçok tümör çeşidi tarafından kullanıldığından bu yolağa karşı kullanılan inhibitörlerin geniş bir terapötik etkinliğinin olabileceği düşünülmektedir. Tekli tedavide bu inhibitörlerin hiçbiri ile faz 1 çalışmalarda önemli cevap oranları elde edilememiş olup yüksek dozların kısa sürelerde verilmesi ve değişik yolaklara etkili olabilecek ilaçların kombine edilmesi gibi diğer seçenekler araştırılmaktadır.

Reactive Oxygen Species: Induced Epigenetic Modification in the Expression Pattern of Oncogenic Proteins

Chapter

Sep 2022

MET kinase inhibitor reverses resistance to entrectinib induced by hepatocyte growth factor in tumors with NTRK1 or ROS1 rearrangements

Article

Full-text available

Nov 2022

Background: Entrectinib is an effective drug for treating solid tumors with NTRK gene rearrangement and non-small cell lung cancer (NSCLC) with ROS1 gene rearrangement. However, its efficacy is limited by tolerance and acquired resistance, the mechanisms of which are not fully understood. The growth factors produced by the tumor microenvironment, including hepatocyte growth factor (HGF) produced by tumor-associated fibroblasts, critically affect the sensitivity to targeted drugs. Methods: We investigated whether growth factors that can be produced by the microenvironment affect sensitivity of NTRK1-rearranged colon cancer KM12SM cells and ROS1-rearranged NSCLC HCC78 cells to entrectinib both in vitro and in vivo. Results: Among the growth factors assessed, HGF most potently induced entrectinib resistance in KM12SM and HCC78 cells by activating its receptor MET. HGF-induced entrectinib resistance was reversed by the active-HGF-specific macrocyclic peptide HiP-8 and the MET kinase inhibitor capmatinib in vitro. In addition, HGF-producing fibroblasts promoted entrectinib resistance in vitro (culture model) and in vivo (subcutaneous tumor model). The use of capmatinib circumvented entrectinib resistance in a subcutaneous tumor model inoculated with KM12SM and HGF-producing fibroblasts. Conclusion: Our findings suggest that growth factors in the tumor microenvironment, such as HGF, may induce resistance to entrectinib in tumors with NTRK1 or ROS1 rearrangements. Our results further suggest that optimally co-administering inhibitors of resistance-inducing growth factors may maximize the therapeutic efficacy of entrectinib.

The 8p11 myeloproliferative syndrome: Genotypic and phenotypic classification and targeted therapy

Article

Full-text available

Nov 2022

EMS(8p11 myeloproliferative syndrome, EMS) is an aggressive hematological neoplasm with/without eosinophilia caused by a rearrangement of the FGFR1 gene at 8p11-12. It was found that all cases carry chromosome abnormalities at the molecular level, not only the previously reported chromosome translocation and insertion but also a chromosome inversion. These abnormalities produced 17 FGFR1 fusion genes, of which the most common partner genes are ZNF198 on 13q11-12 and BCR of 22q11.2. The clinical manifestations can develop into AML (acute myeloid leukemia), T-LBL (T-cell lymphoblastic lymphoma), CML (chronic myeloid leukemia), CMML (chronic monomyelocytic leukemia), or mixed phenotype acute leukemia (MPAL). Most patients are resistant to traditional chemotherapy, and a minority of patients achieve long-term clinical remission after stem cell transplantation. Recently, the therapeutic effect of targeted tyrosine kinase inhibitors (such as pemigatinib and infigratinib) in 8p11 has been confirmed in vitro and clinical trials. The TKIs may become an 8p11 treatment option as an alternative to hematopoietic stem cell transplantation, which is worthy of further study.

White Paper: Mimetics of Class 2 Tumor Suppressor Proteins as Novel Drug Candidates for Personalized Cancer Therapy

Article

Full-text available

Sep 2022

The aim of our proposed concept is to find new target structures for combating cancers with unmet medical needs. This, unfortunately, still applies to the majority of the clinically most relevant tumor entities such as, for example, liver cancer, pancreatic cancer, and many others. Current target structures almost all belong to the class of oncogenic proteins caused by tumor-specific genetic alterations, such as activating mutations, gene fusions, or gene amplifications, often referred to as cancer “driver alterations” or just “drivers.” However, restoring the lost function of tumor suppressor genes (TSGs) could also be a valid approach to treating cancer. TSG-derived proteins are usually considered as control systems of cells against oncogenic properties; thus, they represent the brakes in the “car-of-life.” Restoring these tumor-defective brakes by gene therapy has not been successful so far, with a few exceptions. It can be assumed that most TSGs are not being inactivated by genetic alteration (class 1 TSGs) but rather by epigenetic silencing (class 2 TSGs or short “C2TSGs”). Reactivation of C2TSGs in cancer therapy is being addressed by the use of DNA demethylating agents and histone deacetylase inhibitors which act on the whole cancer cell genome. These epigenetic therapies have neither been particularly successful, probably because they are “shotgun” approaches that, although acting on C2TSGs, may also reactivate epigenetically silenced oncogenic sequences in the genome. Thus, new strategies are needed to exploit the therapeutic potential of C2TSGs, which have also been named DNA methylation cancer driver genes or “DNAme drivers” recently. Here we present a concept for a new translational and therapeutic approach that focuses on the phenotypic imitation (“mimesis”) of proteins encoded by highly disease-relevant C2TSGs/DNAme drivers. Molecular knowledge on C2TSGs is used in two complementary approaches having the translational concept of defining mimetic drugs in common: First, a concept is presented how truncated and/or genetically engineered C2TSG proteins, consisting solely of domains with defined tumor suppressive function can be developed as biologicals. Second, a method is described for identifying small molecules that can mimic the effect of the C2TSG protein lost in the cancer cell. Both approaches should open up a new, previously untapped discovery space for anticancer drugs.

Dual therapeutic approach to modulate Glycogen Synthase kinase −3 beta (GSK-3Β) and inhibitor of nuclear factor kappa kinase-beta (IKK-β) receptors by in silico designing of inhibitors

Article

May 2022
J MOL GRAPH MODEL

Cancer malignancies require the application of advanced strategies leading to the development of novel theranostic. Quite often drugs target a variety of receptors in the cell signaling cascades that could be explored to combat aggressive tumors. Herein, two receptors that are over-expressed during the diagnosis of breast cancer are used as the primary drug targets, inclusively Glycogen Synthase kinase −3 beta (GSK-3Β) and Inhibitor of nuclear factor kappa kinase-beta (IKK-β). Dual-targeting inhibitors pave the way for a challenging pathway in the treatment of aberrant tumor progression. The present study involves the observation of similarities in the structure of the receptors, along with the designing of novel therapeutics that act on them by molecular docking followed by a pharmacokinetic screening approach. A 3D QSAR modeling study is performed to approach the functionality of the bioactive conformer molecules. Additionally, Molecular Dynamic Simulation parameters are used for the validation of the drug complexes. Already available inhibitors are used as reference compounds and a library of analogs generated for these compounds from the PubChem database has been used for in silico designing of novel inhibitors. Molecular Docking and ADME analysis narrowed down the vast library of compounds to two specific classes of chemical compounds. Molecular Dynamic simulation studies used for the selection of the novel moieties showed significant superiority in their stability studies and binding trajectories resulted in two novel molecules A6 and B3 that could inhibit the kinase receptors. The current work involves computational designing of therapeutics targeting two major oncogenic proteins.

Initial Phase I Safety Study of Gedatolisib plus Cofetuzumab Pelidotin for Patients with Metastatic Triple-Negative Breast Cancer

Article

May 2022

Purpose: The PI3K pathway is dysregulated in the majority of triple-negative breast cancer(TNBCs), yet single agent inhibition of PI3K has been ineffective in TNBC. PI3K inhibition leads to an immediate compensatory up-regulation of the Wnt pathway. Dual targeting of both pathways is highly synergistic against TNBC models in vitro and in vivo. We initiated a Phase I clinical trial combining gedatolisib, a pan-class I isoform PI3K/mTOR inhibitor, and cofetuzumab pelidotin, an antibody-drug conjugate against the cell-surface PTK7 protein (Wnt pathway co-receptor) with an auristatin payload. Experimental design: Participants(pts) had metastatic TNBC or ER low (ER and PgR<5%, HER2-negative) breast cancer, and had received at least one prior chemotherapy for advanced disease. The primary objective was safety. Secondary endpoints included objective response(ORR), clinical benefit at 18 weeks(CB18), progression-free survival(PFS), and correlative analyses. Results: 18 pts were enrolled in 3 dose cohorts: gedatolisib 110 mg weekly + cofetuzumab pelidotin 1.4mg/kg every 3 weeks (n=4), 180mg + 1.4mg/kg (n=3), and 180mg + 2.8mg/kg (n=11). Nausea, anorexia, fatigue, and mucositis were common but rarely reached {greater than or equal to} Grade 3 severity. Myelosuppression was uncommon. ORR was 16.7% (3/18). An additional 3 pts had stable disease, of these 2 had stable disease for >18 weeks; CB18 was 27.8%. Median PFS was 2.0 months (95%CI for PFS:1.2-6.2). Pts with clinical benefit were enriched with genomic alterations in the PI3K and PTK7 pathways. Conclusions: The combination of gedatolisib + cofetuzumab pelidotin was well tolerated and demonstrated promising clinical activity. Further investigation of this drug combination in metastatic TNBC is warranted.

ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer

Article

May 2022
DEV CELL

Pancreatic ductal adenocarcinoma (PDA) cells reprogram their transcriptional and metabolic programs to survive the nutrient-poor tumor microenvironment. Through in vivo CRISPR screening, we discovered islet-2 (ISL2) as a candidate tumor suppressor that modulates aggressive PDA growth. Notably, ISL2, a nuclear and chromatin-associated transcription factor, is epigenetically silenced in PDA tumors and high promoter DNA methylation or its reduced expression correlates with poor patient survival. The exogenous ISL2 expression or CRISPR-mediated upregulation of the endogenous loci reduces cell proliferation. Mechanistically, ISL2 regulates the expression of metabolic genes, and its depletion increases oxidative phosphorylation (OXPHOS). As such, ISL2-depleted human PDA cells are sensitive to the inhibitors of mitochondrial complex I in vitro and in vivo. Spatial transcriptomic analysis shows heterogeneous intratumoral ISL2 expression, which correlates with the expression of critical metabolic genes. These findings nominate ISL2 as a putative tumor suppressor whose inactivation leads to increased mitochondrial metabolism that may be exploitable therapeutically.

The human AP-endonuclease 1 (APE1) is a DNA G-quadruplex structure binding protein and regulates KRAS expression in pancreatic ductal adenocarcinoma cells

Article

Full-text available

Mar 2022

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive types of cancer, is characterized by aberrant activity of oncogenic KRAS. A nuclease-hypersensitive GC-rich region in KRAS promoter can fold into a four-stranded DNA secondary structure called G-quadruplex (G4), known to regulate KRAS expression. However, the factors that regulate stable G4 formation in the genome and KRAS expression in PDAC are largely unknown. Here, we show that APE1 (apurinic/apyrimidinic endonuclease 1), a multifunctional DNA repair enzyme, is a G4-binding protein, and loss of APE1 abrogates the formation of stable G4 structures in cells. Recombinant APE1 binds to KRAS promoter G4 structure with high affinity and promotes G4 folding in vitro. Knockdown of APE1 reduces MAZ transcription factor loading onto the KRAS promoter, thus reducing KRAS expression in PDAC cells. Moreover, downregulation of APE1 sensitizes PDAC cells to chemotherapeutic drugs in vitro and in vivo. We also demonstrate that PDAC patients’ tissue samples have elevated levels of both APE1 and G4 DNA. Our findings unravel a critical role of APE1 in regulating stable G4 formation and KRAS expression in PDAC and highlight G4 structures as genomic features with potential application as a novel prognostic marker and therapeutic target in PDAC.

LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer

Article

Full-text available

Feb 2022

LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the cancer state that stems from Lkb1 deficiency can be reverted remains unknown. To identify the processes governed by LKB1 in vivo, we generated an allele which enables Lkb1 inactivation at tumor initiation and subsequent Lkb1 restoration in established tumors. Restoration of Lkb1 in oncogenic KRAS-driven lung tumors suppressed proliferation and led to tumor stasis. Lkb1 restoration activated targets of C/EBP transcription factors and drove neoplastic cells from a progenitor-like state to a less proliferative alveolar type II cell-like state. We show that C/EBP transcription factors govern a subset of genes that are induced by LKB1 and depend upon NKX2-1. We also demonstrate that a defining factor of the alveolar type II lineage, C/EBPα, constrains oncogenic KRAS-driven lung tumor growth in vivo. Thus, this key tumor suppressor regulates lineage-specific transcription factors, thereby constraining lung tumor development through enforced differentiation.

Design, synthesis, antineoplastic activity of new pyrazolo[3,4-d]pyrimidine derivatives as dual CDK2/GSK3β kinase inhibitors; molecular docking study, and ADME prediction

Article

Jun 2024
BIOORG CHEM

In the current study, novel pyrazolo[3,4-d]pyrimidine derivatives 5a–h were designed and synthesized as targeted anti-cancer agents through dual CDK2/GSK-3β inhibition. The designed compounds demonstrated moderate to potent activity on the evaluated cancer cell lines (MCF-7 and T-47D). Compounds 5c and 5 g showed the most promising cytotoxic activity against the tested cell lines surpassing that of the used reference standard; staurosporine. On the other hand, both compounds showed good safety and tolerability on normal fibroblast cell line (MCR5). The final compounds 5c and 5 g showed a promising dual CDK2/GSK-3β inhibitory activity with IC50 of 0.244 and 0.128 μM, respectively, against CDK2, and IC50 of 0.317 and 0.160 μM, respectively, against GSK-3β. Investigating the effect of compounds 5c and 5 g on CDK2 and GSK-3β downstream cascades showed that they reduced the relative cellular content of phosphorylated RB1 and β-catenin compared to that in the untreated MCF-7 cells. Moreover, compounds 5c and 5 g showed a reasonable selective inhibition against the target kinases CDK2/GSK-3β in comparison to a set of seven off-target kinases. Furthermore, the most potent compound 5 g caused cell cycle arrest at the S phase in MCF-7 cells preventing the cells’ progression to G2/M phase inducing cell apoptosis. Molecular docking studies showed that the final pyrazolo[3,4-d]pyrimidine derivatives have analogous binding modes in the target kinases interacting with the hinge region key amino acids. Molecular dynamics simulations confirmed the predicted binding mode by molecular docking. Moreover, in silico predictions indicated their favorable physicochemical and pharmacokinetic properties in addition to their promising cytotoxic activity.

DNA G-quadruplexes as Targets for Natural Product Drug Discovery

Article

May 2024

Non-oncogene dependencies: Novel opportunities for cancer therapy

Article

May 2024

ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework

Article

Full-text available

Mar 2024

At least 40% of human cancers are associated with aberrant ERK pathway activity (ERKp). Inhibitors targeting various effectors within the ERKp have been developed and explored for over two decades. Conversely, a substantial body of evidence suggests that both normal human cells and, notably to a greater extent, cancer cells exhibit susceptibility to hyperactivation of ERKp. However, this vulnerability of cancer cells remains relatively unexplored. In this review, we reexamine the evidence on the selective lethality of highly elevated ERKp activity in human cancer cells of varying backgrounds. We synthesize the insights proposed for harnessing this vulnerability of ERK-associated cancers for therapeutical approaches and contextualize these insights within established pharmacological cancer-targeting models. Moreover, we compile the intriguing preclinical findings of ERK pathway agonism in diverse cancer models. Lastly, we present a conceptual framework for target discovery regarding ERKp agonism, emphasizing the utilization of mutual exclusivity among oncogenes to develop novel targeted therapies for precision oncology.

Targeting EphA2: a promising strategy to overcome chemoresistance and drug resistance in cancer

Article

Full-text available

Feb 2024
J MOL MED-JMM

Erythropoietin-producing hepatocellular A2 (EphA2) is a vital member of the Eph tyrosine kinase receptor family and has been associated with developmental processes. However, it is often overexpressed in tumors and correlates with cancer progression and worse prognosis due to the activation of its noncanonical signaling pathway. Throughout cancer treatment, the emergence of drug-resistant tumor cells is relatively common. Since the early 2000s, researchers have focused on understanding the role of EphA2 in promoting drug resistance in different types of cancer, as well as finding efficient and secure EphA2 inhibitors. In this review, the current knowledge regarding induced resistance by EphA2 in cancer treatment is summarized, and the types of cancer that lead to the most cancer-related deaths are highlighted. Some EphA2 inhibitors were also investigated. Regardless of whether the cancer treatment has reached a drug-resistance stage in EphA2-overexpressing tumors, once EphA2 is involved in cancer progression and aggressiveness, targeting EphA2 is a promising therapeutic strategy, especially in combination with other target-drugs for synergistic effect. For that reason, monoclonal antibodies against EphA2 and inhibitors of this receptor should be investigated for efficacy and drug toxicity.

From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer

Article

Full-text available

Feb 2024

Ovarian clear-cell cancer is a rare subtype of epithelial ovarian cancer with unique clinical and biological features. Despite optimal cytoreductive surgery and platinum-based chemotherapy being the standard of care, most patients experience drug resistance and a poor prognosis. Therefore, novel therapeutic approaches have been developed, including immune checkpoint blockade, angiogenesis-targeted therapy, ARID1A synthetic lethal interactions, targeting hepatocyte nuclear factor 1β, and ferroptosis. Refining predictive biomarkers can lead to more personalized medicine, identifying patients who would benefit from chemotherapy, targeted therapy, or immunotherapy. Collaboration between academic research groups is crucial for developing prognostic outcomes and conducting clinical trials to advance treatment for ovarian clear-cell cancer. Immediate progress is essential, and research efforts should prioritize the development of more effective therapeutic strategies to benefit all patients.

Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy

Article

Full-text available

Feb 2024

Cancer is a leading cause of death worldwide. Targeted therapies aimed at key oncogenic driver mutations in combination with chemotherapy and radiotherapy as well as immunotherapy have benefited cancer patients considerably. Tumor protein p53 (TP53), a crucial tumor suppressor gene encoding p53, regulates numerous downstream genes and cellular phenotypes in response to various stressors. The affected genes are involved in diverse processes, including cell cycle arrest, DNA repair, cellular senescence, metabolic homeostasis, apoptosis, and autophagy. However, accumulating recent studies have continued to reveal novel and unexpected functions of p53 in governing the fate of tumors, for example, functions in ferroptosis, immunity, the tumor microenvironment and microbiome metabolism. Among the possibilities, the evolutionary plasticity of p53 is the most controversial, partially due to the dizzying array of biological functions that have been attributed to different regulatory mechanisms of p53 signaling. Nearly 40 years after its discovery, this key tumor suppressor remains somewhat enigmatic. The intricate and diverse functions of p53 in regulating cell fate during cancer treatment are only the tip of the iceberg with respect to its equally complicated structural biology, which has been painstakingly revealed. Additionally, TP53 mutation is one of the most significant genetic alterations in cancer, contributing to rapid cancer cell growth and tumor progression. Here, we summarized recent advances that implicate altered p53 in modulating the response to various cancer therapies, including chemotherapy, radiotherapy, and immunotherapy. Furthermore, we also discussed potential strategies for targeting p53 as a therapeutic option for cancer.

Methodical selected coptisine attenuates the malignancy of cholangiocarcinoma through the blockade of EGFR signalling

Article

Jan 2024

New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer

Article

Full-text available

Nov 2023

Simple Summary The Hippo pathway is crucial for regulating cell growth, organ size, and tissue regeneration. When this pathway goes awry, it can lead to uncontrolled cell growth, tumor spread, and resistance to cancer treatments. This review covers recent progress in understanding how the Hippo pathway is involved in cancer and discusses potential therapies targeting this pathway. In addition, we address ongoing debates and provide perspectives on debated topics in this field. Abstract The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation of Hippo pathway components not only contributes to tumor growth and metastasis, but also renders tumors resistant to therapies. This review delves into recent research on YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ’s biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field.

Transcriptional background effects on a tumor driver gene in different pigment cell types of medaka

Article

Oct 2023

The Xiphophorus melanoma receptor kinase gene, xmrk , is a bona fide oncogene driving melanocyte tumorigenesis of Xiphophorus fish. When ectopically expressed in medaka, it not only induces development of several pigment cell tumor types in different strains of medaka but also induces different tumor types within the same animal, suggesting its oncogenic activity has a transcriptomic background effect. Although the central pathways that xmrk utilizes to lead to melanomagenesis are well documented, genes and genetic pathways that modulate the oncogenic effect and alter the course of disease have not been studied so far. To understand how the genetic networks between different histocytes of xmrk ‐driven tumors are composed, we isolated two types of tumors, melanoma and xanthoerythrophoroma, from the same xmrk transgenic medaka individuals, established the transcriptional profiles of both xmrk ‐driven tumors, and compared (1) genes that are co‐expressed with xmrk in both tumor types, and (2) differentially expressed genes and their associated molecular functions, between the two tumor types. Transcriptomic comparisons between the two tumor types show melanoma and xanthoerythrophoroma are characterized by transcriptional features representing varied functions, indicating distinct molecular interactions between the driving oncogene and the cell‐type‐specific transcriptomes. Melanoma tumors exhibit gene signatures that are relevant to proliferation and invasion, while xanthoerythrophoroma tumors are characterized by expression profiles related to metabolism and DNA repair. We conclude the transcriptomic backgrounds, exemplified by cell‐type‐specific genes that are downstream of xmrk effected signaling pathways, contribute the potential to change the course of tumor development and may affect overall tumor outcomes.

A Cell‐Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer‐Specific Synthetic Lethality

Article

Full-text available

Oct 2023

Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof‐of‐principle evidence is presented that a cell‐penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene‐addicted cancer cells through transcription activity‐independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2‐p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome‐wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C‐resistant cancers. This study enhances the understanding of ACP52C‐induced cancer‐specific apoptosis induction and supports the use of ACP52C in anticancer drug development.

New therapies for clear cell ovarian carcinoma

Article

Mar 2023
INT J GYNECOL CANCER

Ovarian clear cell carcinoma is a rare subtype of epithelial ovarian cancer with unique clinicopathological features. The most common genetic aberration observed is loss of function ARID1A mutations. Advanced and recurrent ovarian clear cell carcinoma is characterized by resistance to standard-of-care cytotoxic chemotherapy and a poor prognosis. Despite the distinct molecular features of ovarian clear cell carcinoma, current treatments for this subtype of epithelial ovarian cancer are based on clinical trials which predominantly recruited patients with high grade serous ovarian carcinoma. These factors have encouraged researchers to develop novel treatment strategies specifically for ovarian clear cell carcinoma which are currently being tested in the context of clinical trials. These new treatment strategies currently focus on three key areas: immune checkpoint blockade, targeting angiogenesis, and exploiting ARID1A synthetic lethal interactions. Rational combinations of these strategies are being assessed in clinical trials. Despite the progress made in identifying new treatments for ovarian clear cell carcinoma, predictive biomarkers to better define those patients likely to respond to new treatments remain to be elucidated. Additional future challenges which may be addressed through international collaboration include the need for randomized trials in a rare disease and establishing the relative sequencing of these novel treatments.

Therapeutic Targeting of Cancer Cells

Chapter

Jan 2020

Defektif Homolog Rekombinasyon DNA Tamiri ve PARP İnhibisyonu Arasındaki Sentetik Letal EtkileşimSynthetic Lethal Interaction between Defective Homologous Recombination DNA Repair and PARP Inhibition

Article

Full-text available

Dec 2022

İnsan hücreleri endojen ve eksojen nedenlerle oluşan genomik hasarlara karşı kompleks bir DNA hasar yanıt mekanizmasına sahiptir. Hücreler, DNA hasar yanıt işlevsizliği durumunda onarılmadıklarından genom stabilitesini tehdit eden çeşitli DNA lezyonlarını biriktirmeye başlar. Yetersiz DNA hasar yanıt aktivitesi; neoplastik transformasyona, antikanser ilaç direncine ve ilgili tedaviler neticesinde oluşan ciddi yan etkilere neden olmanın yanı sıra, tedavi yanıtının tahmininde kullanılabilir bir biyogösterge veya kanser hücrelerini mevcut tedavilere karşı daha duyarlı hale getirebilecek farmakolojik bir hedef olarak da kullanılabilmektedir. Poli (ADP-riboz) (PARP) enzimleri, DNA tek zincir kırıklarının onarılması dahil birçok hücresel mekanizmada rol oynamaktadır. BRCA1/2 proteinleri ise DNA çift zincir kırıklarının homolog rekombinasyon yolağıyla tamir edilmesinde görev almaktadır. Yapılan çalışmalar, BRCA1/2 mutasyonu neticesinde homolog rekombinasyon defektif hale gelen hücrelerin PARP inhibitörlerine karşı hassasiyet kazandığı göstermiştir. BRCA1/2 ve PARP arasında tanımlanan söz konusu sentetik letal etkileşimin başarılı klinik uygulaması, araştırmacıları homolog rekombinasyon durumunu bildirecek farklı biyogöstergeleri araştırmaya ve PARP inhibitör direncinin üstesinden gelmek için diğer potansiyel sentetik letal etkileşimleri ortaya çıkarmaya yönlendirmiştir. Bu derlemede öncelikle DNA hasar yanıt yolağının mevcut durumu özetlenmiş, sonrasında HR tamir sistemi ve PARP inhibisyonu arasındaki sentetik letalite anlatılmıştır.

Idiopathic pulmonary fibrosis and lung cancer: targeting the complexity of the pharmacological interconnection

Article

Nov 2022

Introduction Many data already suggested that cancer and IPF are underlined by a number of common pathogenic biologic pathways. However fewer data regards the interconnections, in terms of synergy or increased toxicities, of drugs used in cancer and IPF. Particularly, how the specific therapy influences the concurrent condition and prognostic factors of response in patients with both lung cancer and IPF are far to be clarified. Similarly, identification of features of IPF patients with higher risk of developing pulmonary adverse events when treated with chemotherapy, immune checkpoint inhibitors, TKIs, or radio-therapy is of primary importance in clinical practice. Areas covered We will discuss the scientific rationale, based on the extensive analysis of literature data, by consulting several databases for combining anticancer and antifibrotic treatments and for the design of novel therapeutic strategies. The role of immunotherapy in cancer aroused in IPF context will be discussed with specific interested, based on the continuously increasing role of immune checkpoint inhibition against lung tumors. Expert opinion This work will help to improve knowledge according to a multidisciplinary perspective on a rare and orphan subset of patients, as those affected by cancer and IPF which identify an unmet clinical need. A better management during each phase of disease progression will require the design innovative trials and the development of new drugs and molecules both in the oncologic and respiratory medicine pipelines.

An integrated approach to dissecting oncogene addition implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance

Article

Full-text available

Aug 2011
GENE DEV

Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations-a phenomenon dubbed "oncogene addiction." Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9-a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential and poor prognosis in human AML. Accordingly, partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis, indicating that strategies to inhibit Myb-dependent aberrant self-renewal programs hold promise as effective and cancer-specific therapeutics. Together, our results identify Myb as a critical mediator of oncogene addiction in AML, delineate relevant Myb target genes that are amenable to pharmacologic inhibition, and establish a general approach for dissecting oncogene addiction in vivo.

Development of optimized self nano emulsifying systems of entrectinib for enhanced dissolution

Preprint

Full-text available

Aug 2022

Entrectinib is a novel potent anticancer drug with poor aqueous solubility. A supersaturable self nano emulsifying drug delivery system of entrectinib is developed using a super saturation promoter. The components of the isotropic mixture of SNEDDS were selected based on solubility and emulsification study. The optimum composition was identified using phase diagrams and further optimized by mixture design. The supersaturated SNEDDS was prepared using HPMC K4M as precipitation inhibitor. The droplet of sSNEDDS ranges from 118.42 ± 1.26 to 128.34 ± 0.63 nm with PDI values ranges from 0.112 to 0.204, which is significantly smaller than that observed with plain SNEDDS. The percent transmittance of the diluted formulation was found to be 98.78 ± 0.74. The viscosity was found to be 528 ± 32 centipoises indicating the good flow ability. FTIR and DSC studies indicated the amorphization of the drug. The dissolution profile of sSNEDDS indicated the faster release of drug compared to both pure drug suspension and SNEDDS formulation. The drug release rate is directly proportional to the concentration of the drug. The drug release from the insoluble matrix is a square root of time dependent Fickian diffusion process. The formulation was found to be stable and transparent at all pH values and the percent transmittance was more than 95%. No significant difference was observed with all the samples exposed at different storage conditions. This study demonstrated the feasibility of stabilizing and improving the in-vitro performance of SNEDDS by incorporating HPMC K4M as precipitation inhibitor.

Targeting MET amplification in Gastro-oesophageal (GO) malignancies and overcoming MET inhibitor resistance: challenges and opportunities

Article

Jun 2022

Introduction: MET, the hepatocyte growth factor receptor is amplified in 8% of gastro-oesophageal (GO) malignancies and associated with poor prognosis. Therapeutic targeting of MET amplification and MET mutations, has the potential to improve outcomes for patients with GO cancers (GOC). Areas covered: The efficacy of MET inhibition (METi) in preclinical studies has not translated into meaningful improvements in the treatment paradigm for unselected GOC. MET amplification has been proposed as a superior modality for patient selection, however even if confirmed, frequency and duration of response to METi is limited by rapid activation of primary and secondary resistance pathways. These observations illustrate the challenges inherent in the application of precision oncology predicated on the theory of oncogenic addiction. Expert opinion: A standardised definition of MET positivity is critical to enhance patient selection. Early successes targeting the METex14 skipping mutation demonstrate the potent therapeutic effects of METi in a clearly molecularly defined cohort. There is robust preclinical rationale and early phase data supporting exploitation of immune system interaction with MET. Pragmatic investigation of rational therapeutic combinations based on molecular profiling of both primary and metastatic disease sites with sequential circulating tumour DNA analysis can inform successful clinical development of METi agents in GOC.

Développement et caractérisation de l'effet thérapeutique de peptides pénétrants dérivés de la protéine AAC-11 dans le contexte de cancers cutanés et/ou hématologiques.

Thesis

Jun 2020

Justine Habault

L’équipe du Dr. Poyet s’intéresse à l’étude des interactions protéine-protéine (PPIs) dans le contrôle de l’apoptose et leur modulation dans le cadre de nouvelles stratégies médicamenteuses et a démontré le rôle important de la protéine AAC-11 pour le développement et la progression tumorale. AAC-11 est une protéine anti-apoptotique, surexprimée dans de nombreux tissus et cellules néoplasiques. Elle possède un rôle crucial dans la survie de ces cellules et leur sensibilité aux agents anti-cancéreux, dû à des PPIs impliquant son domaine Leucin-Zipper (LZ).Notre équipe a donc eu l’idée de concevoir des peptides pénétrants (CPPs) dérivés du domaine LZ d’AAC-11 et agissant comme inhibiteurs compétitifs de son activité. Les CPPs sont de petites séquences d’acides aminés capables de traverser la membrane plasmique des cellules pour y délivrer un cargo. Ils ont l’avantage d’être faciles à synthétiser et à modifier et surtout d’être généralement non-toxiques in vivo. Nos peptides sont constitués de deux domaines : la pénétratine (séquence de pénétration cellulaire), couplée à des portions du domaine LZ d’AAC-11. Ces peptides appelés LZDPs ont été brevetés (PCT/EP2015/053307) sur la base de la démonstration de leur activité anti-tumorale dans divers modèles de cancers, parmi lesquels le mélanome.Mon projet de thèse visait à évaluer les propriétés anti-tumorales de ces peptides dans d’autres types de cancers, en particulier le Syndrome de Sézary (SS) et les Leucémies Aigües Myéloïdes (LAMs). Les résultats obtenus dans ces pathologies ont mis en évidence un fort effet cytotoxique des peptides LZDPs vis-à-vis des cellules malignes, mais pas des cellules saines environnantes. Cette activité anti-tumorale spécifique est non seulement observée in vitro sur des lignées cellulaires, mais aussi ex vivo sur des prélèvements de patients et in vivo dans des modèles murins pré-cliniques.J’avais également pour objectif d’approfondir nos connaissances concernant le mécanisme d’action des peptides LZDPs. Les données obtenues au cours de ma thèse ont montré qu’ils agissaient en induisant une rupture de la membrane des cellules cancéreuses qui semble due à l’interaction avec un ou des partenaires exprimés uniquement à la membrane des cellules tumorales. Un de ces partenaires est la protéine PAK1, exprimée à la membrane des cellules de Sézary et des cellules leucémiques et dont la présence est nécessaire à l’activité membranolytique des peptides. PAK1 est particulièrement intéressante car elle est connue pour être impliquée dans plusieurs étapes de la tumorigénèse, et son interaction avec AAC-11 pourrait potentiellement expliquer le développement de certains cancers.Fait intéressant, nos résultats indiquent que les peptides LZDPs induisent une mort cellulaire immunogène des cellules cancéreuses. Dans des modèles murins immunocompétents, nous avons mis en évidence que cela permettait l’activation du système immunitaire. Ainsi, dans ces modèles, il est possible d’utiliser les lysats cellulaires obtenus après exposition de cellules cancéreuses aux peptides en tant que vaccins prophylactiques ou thérapeutiques.Enfin, un autre axe de ma thèse consistait à optimiser la séquence de pénétration et la séquence active des peptides dérivés d’AAC-11. D’une part, nous avons amélioré la portion LZ du peptide, en concevant des peptides plus courts, conservant les propriétés anti-tumorales du peptide original. D’autre part, nous avons construit une séquence de pénétration plus courte et plus efficace en termes de pénétration cellulaire que la pénétratine. Les peptides « seconde génération » constitués de cette séquence associée à celle du LZ d’AAC-11 possèdent des propriétés anti-tumorales comparables à celles des peptides de première génération.Forts de ces résultats, nous espérons désormais débuter un ou plusieurs essai(s) clinique(s) dans les contextes du SS et de la LAM, en collaboration avec les équipes médicales de l’hôpital St-Louis.

The Current State of Precision Medicine and Targeted-Cancer Therapies: Where Are We?

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Jan 2022

Attila Seyhan

Precision or personalized medicine is a strategy that allows the selection of specific treatments based on the patient’s genetic or genomic changes that may occur in an individual’s tumor. The goal of precision medicine is simply to deliver the right treatment to the right patient at the right dose and the right time.Precision medicine involves the collection and validation of population-wide data, including multi-omics molecular profiling data such as epigenetic, genetic, genomic, proteomic, and metabolomic alterations to identify targetable/actionable molecular targets. Personalized medicine on the other hand involves the collection and analysis of an individual patient’s tumor or liquid biopsy molecular profiling data and clinical data for their treatment with targeted therapies developed to be specific to those genetic or genomic abnormalities. The process of precision medicine may also involve the use of machine learning algorithms and artificial intelligence (AI) to both design a drug combination based on a patient’s data and follow specific drug dosing regimens.However, there are some challenges. For example, considerations for molecular profiling should include the type of tissues to utilize, timing of profiling in the disease course, comprehensiveness of the molecular panel as well as the interpretation of molecular data, which remains a challenge. Because resistance to targeted therapies is also a concern, resampling and retesting of tumors, including a dynamic sampling of liquid biopsy specimens after clinical progression, may help to make better treatment decisions. In addition, analysis, and interpretation of large molecular profiling datasets to identify clinically relevant markers for disease susceptibility and treatment efficacy and pairing these molecular signatures to specific targeted therapies remains a challenge. Furthermore, successful deployment of both precision and personalized medicine requires their effective integration, with genome-guided drug pairing (driven by population data) followed by AI-guided dynamic therapeutic intervention (driven by individual data).Collectively, the successful deployment of precision medicine requires significant resources ranging from large-scale data generation to analysis capabilities, and coordination and effective collaboration between all relevant stakeholders such as scientists, clinicians, patients, biopharmaceutical companies, insurers, and regulatory agencies.KeywordsPrecision medicinePersonalized medicineBiomarkersOmics technologiesTargeted therapies

The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets

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Full-text available

Apr 2022

The resistance to transcription factor-mediated reprogramming into pluripotent stem cells is one of the distinctive features of cancer cells. Here we dissect the profiles of reprogramming factor binding and the subsequent transcriptional response in cancer cells to reveal its underlying mechanisms. Using clear cell sarcomas (CCSs), we show that the driver oncogene EWS/ATF1 misdirects the reprogramming factors to cancer-specific enhancers and thereby impairs the transcriptional response toward pluripotency that is otherwise provoked. Sensitization to the reprogramming cue is observed in other cancer types when the corresponding oncogenic signals are pharmacologically inhibited. Exploiting this oncogene dependence of the transcriptional “stiffness,” we identify mTOR signaling pathways downstream of EWS/ATF1 and discover that inhibiting mTOR activity substantially attenuates the propagation of CCS cells in vitro and in vivo. Our results demonstrate that the early transcriptional response to cell fate perturbations can be a faithful readout to identify effective therapeutics targets in cancer cells.

Reversibility of acute B-cell leukaemia induced by BCR-ABL1

Article

Full-text available

Jan 2000

Cancer is thought to arise from multiple genetic events that establish irreversible malignancy. A different mechanism might be present in certain leukaemias initiated by a chromosomal translocation. We have taken a new approach to determine if ablation of the genetic abnormality is sufficient for reversion by generating a conditional transgenic model of BCR-ABL1 (also known as BCR-ABL)-induced leukaemia. This oncogene is the result of a reciprocal translocation and is associated with different forms of leukaemia. The most common form, p210 BCR-ABL1, is found in more than 90% of patients with chronic myelogenous leukaemia (CML) and in up to 15% of adult patients with de novoacute lymphoblastic leukaemia (ALL). Efforts to establish a useful transgenic model have been hampered by embryonic lethality when the oncogene is expressed during embryogenesis, by reduced penetrance or by extremely long latency periods. One model uses the 'knock-in' approach to induce leukaemia by p190 BCR-ABL1(ref. 10). Given the limitations of models with p210, we used a different experimental approach. Lethal leukaemia developed within an acceptable time frame in all animals, and complete remission was achieved by suppression of BCR-ABL1expression, even after multiple rounds of induction and reversion. Our results demonstrate that BCR-ABL1is required for both induction and maintenance of leukaemia.

erbB-2 antisense oligonucleotides inhibit the proliferation of breast carcinoma cells with erbB-2 oncogene amplification

Article

Full-text available

Dec 1994

Amplification and overexpression of the erbB-2 oncogene is an unfavourable prognostic marker in human breast cancer and occurs in approximately 25% of breast carcinomas. We used erbB-2 antisense oligonucleotides to inhibit the proliferation of human breast cancer cell lines. erbB-2 antisense oligonucleotides (20 microM) inhibited the growth and DNA synthesis of breast cancer cell lines with an amplified erbB-2 gene by up to 60%. Control complementary sense oligonucleotides did not inhibit cellular proliferation at the same concentration but showed inhibitory effects at higher concentrations. There was no specific effect of erbB-2 antisense oligonucleotides on breast cancer cell lines that had no amplification of erbB-2. erbB-2 antisense oligonucleotides reduced erbB-2 protein levels, measured by immunohistochemistry, in a dose-dependent manner. erbB-2 sense oligonucleotides did not decrease the levels of erbB-2 protein. These data indicate that erbB-2 antisense oligonucleotides induce a specific inhibition of erbB-2 protein expression and that erbB-2 gene overexpression is important for the proliferation of the breast cancer cells that have been selected for erbB-2 amplification. Images Figure 3

Antisense to cyclin D1 inhibits the growth and tumorigenicity of human colon cancer cells

Article

Full-text available

May 1997

Cyclin D1 plays an important role in regulating the progression of cells through the G1 phase of the cell cycle. This gene is frequently overexpressed in human colon cancer. To address the role of cyclin D1 in growth control and tumorigenesis in this disease, we have overexpressed an antisense cyclin D1 cDNA construct in the human colon cancer cell line SW480E8, which expresses high levels of cyclin D1. The integration and expression of the antisense construct was verified by Southern and Northern blot analyses, respectively, and resulted in decreased expression of the cyclin D1 protein. This was associated with decreased levels of the Rb and p27Kip1 proteins. In addition, the hypophosphorylated form of Rb was increased in these cells. The SW480E8 antisense cyclin D1 cells displayed an increased doubling time, a decrease in saturation density, decreased plating efficiency and anchorage-independent growth, and a loss of tumorigenicity in nude mice. These findings provide direct evidence that increased expression of cyclin D1 in colon tumor cells contributes to their abnormal growth and tumorigenicity. The ability to revert the transformed phenotype of these cells with antisense cyclin D1 suggests that cyclin D1 or its associated cyclin-dependent kinase 4 may be useful targets in the therapy of colon cancer.

Disorders in cell circuitry associated with multistage carcinogenesis: Exploitable targets for cancer prevention and therapy

Article

Full-text available

Jan 1998

The development of a malignant tumor involves the progressive acquisition of mutations and epigenetic abnormalities in multiple genes that have highly diverse functions. Some of these genes code for pathways of signal transduction that mediate the action of growth factors. The enzyme protein kinase C plays an important role in these events and in the process of tumor promotion. Therefore, we examined the effects of three inhibitors of protein kinase C, CGP 41251, RO 31-8220, and calphostin C, on human glioblastoma cells. These compounds inhibited growth and induced apoptosis; these activities were associated with a decrease in the level of CDC2 and cyclin B1/CDC2-associated kinase activity. This may explain why the treated cells accumulated in G2-M. In a separate series of studies, we examined abnormalities in cell cycle control genes in human cancer. We have found that cyclin D1 is frequently overexpressed in a variety of human cancers. Mechanistic studies indicate that cyclin D1 can play a critical role in carcinogenesis because: overexpression enhances cell transformation and tumorigenesis; introduction of an antisense cyclin D1 cDNA into either human esophageal or colon cancer cells reverts their malignant phenotype; and overexpression of cyclin D1 can enhance the amplification of other genes. The latter finding suggests that cyclin D1 can enhance genomic instability and, thereby, the process of tumor progression. Therefore, inhibitors of the function of cyclin D1 may be useful in both cancer chemoprevention and therapy. We obtained evidence for the existence of homeostatic feedback loops between cyclins D1 or E and the cell cycle inhibitory protein p27Kip1. On the basis of these and other findings, we hypothesize that, because of their disordered circuitry, cancer cells suffer from "gene addiction" and "gene hypersensitivity," disorders that might be exploited in both cancer prevention and therapy.

Inhibition of cyclin D1 expression in human pancreatic cancer cells is associated with increased chemosensitivity and decreased expression of multiple chemoresistance genes

Article

Full-text available

Aug 1999

Cyclin D1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. Inhibition of cyclin D1 expression has been recently shown (M. Kornmann, et al., J. Clin. Invest, 101: 344-352, 1998) to suppress pancreatic cancer cell growth and increase cytotoxic actions of cisplatinum. The aim of the present study was to determine whether inhibition of cyclin D1 expression also modulates the effects of other antineoplastic drugs and whether it is associated with alterations in the level of expression of drug resistance genes. The suppression of cyclin D1 expression after the stable transfection of a cyclin D1 antisense construct in PANC-1 and COLO-357 human pancreatic cancer cells resulted in a significant increase in sensitivity to the fluoropyrimidines 5-fluorouracil and 5-fluoro-2'-deoxyuridine and to mitoxantrone. All of the antisense-expressing dones exhibited a decrease in thymidylate synthase and an increase in thymidine phosphorylase mRNA expression as determined by reverse transcription-PCR analysis and decreased levels of MDR-1 and MRP mRNA as determined by Northern blotting. These findings demonstrate that the inhibition of cyclin D1, in addition to suppressing the growth of pancreatic cancer cells, enhances their responsiveness to multiple chemotherapeutic agents and suggest that this effect may be due to the altered expression of several chemoresistance genes.

Gene Expression Profiling, Genetic Networks, and Cellular States: An Integrating Concept for Tumorigenesis and Drug Discovery

Article

Full-text available

Jul 1999

Sui Huang

Genome-wide expression monitoring, a novel tool of functional genomics, is currently used mainly to identify groups of coregulated genes and to discover genes expressed differentially in distinct situations that could serve as drug targets. This descriptive approach. however, fails to extract "distributed" information embedded in the genomic regulatory network and manifested in distinct gene activation profiles. A model based on the formalism of boolean genetic networks in which cellular states are represented by attractors in a discrete dynamic system can serve as a conceptual framework for an integrative interpretation of gene expression profiles. Such a global (genome-wide) view of "gene function" in the regulation of the dynamic relationship between proliferation, differentiation, and apoptosis can provide new insights into cellular homeostasis and the origins of neoplasia. Implications for a rational approach to the identification of new drug targets for cancer treatment are discussed.

c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations

Article

Full-text available

Mar 2001

Although the process of mammary tumorigenesis requires multiple genetic events, it is unclear to what extent carcinogenesis proceeds through preferred secondary pathways following a specific initiating oncogenic event. Similarly, the extent to which established mammary tumors remain dependent on individual mutations for maintenance of the transformed state is unknown. Here we use the tetracycline regulatory system to conditionally express the human c-MYC oncogene in the mammary epithelium of transgenic mice. MYC encodes a transcription factor implicated in multiple human cancers. In particular, amplification and overexpression of c-MYC in human breast cancers is associated with poor prognosis, although the genetic mechanisms by which c-MYC promotes tumor progression are poorly understood. We show that deregulated c-MYC expression in this inducible system results in the formation of invasive mammary adenocarcinomas, many of which fully regress following c-MYC deinduction. Approximately half of these tumors harbor spontaneous activating point mutations in the ras family of proto-oncogenes with a strong preference for Kras2 compared with Hras1. Nearly all tumors lacking activating ras mutations fully regressed following c-MYC deinduction, whereas tumors bearing ras mutations did not, suggesting that secondary mutations in ras contribute to tumor progression. These findings demonstrate that c-MYC-induced mammary tumorigenesis proceeds through a preferred secondary oncogenic pathway involving Kras2.

Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2

Article

Full-text available

Apr 2001

The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.

Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras

Article

Full-text available

Jan 2002
GENE DEV

Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras. Here we show that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation. Through the ability to synchronize tumor initiation in these mice, we have been able to characterize the stages of tumor progression. Of particular significance, this system has led to the identification of a new cell type contributing to the development of pulmonary adenocarcinoma.

Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms

Article

Full-text available

Apr 2002

The primary objectives of this trial were to define the maximum tolerated dose (MTD) and to characterize the toxicities and pharmacokinetics of depsipeptide (FR901228) given on a day-1 and day-5 schedule every 21 days. A secondary objective of the trial was to seek evidence of antineoplastic activity. Patients with advanced or refractory neoplasms received depsipeptide by a 4-h i.v. infusion on days 1 and 5 of a 21-day cycle. On the basis of preclinical data suggesting that depsipeptide may have significant cardiac toxicity, patients were treated while receiving continuous cardiac monitoring and were followed with serial cardiac enzyme determinations, electrocardiograms (ECGs), and nuclear ventriculograms (MUGA scans). The starting dose of the trial was 1 mg/m(2), and dose escalations proceeded through a total of eight dose levels to a maximum of 24.9 mg/m(2). Toxicities were graded using the National Cancer Institute common toxicity criteria, and pharmacokinetics were determined using a liquid chromatography/tandem mass spectrometry method. Patients (37) received a total of 88 cycles of treatment on study (range: one to eight cycles). Dose-limiting toxicity (DLT) was observed, and the MTD exceeded at a dose of 24.9 mg/m(2). The DLTs included grade-3 fatigue (3 patients), grade-3 nausea and vomiting (1 patient), grade-4 thrombocytopenia (2 patients), and grade-4 cardiac arrhythmia (1 patient, atrial fibrillation). The MTD was defined at the seventh dose level (17.8 mg/m(2)). Reversible ST/T changes and mild reversible dysrhythmias were observed on the post-treatment ECG. There were no clinically significant changes in left ventricular ejection fraction. One patient achieved a partial response. The plasma disposition of depsipeptide was well described by a first-order, two-compartment model. The mean volume of distribution, clearance, t(1/2alpha) and t(1/2beta) at a dose of 17.8 mg/m(2) was: 8.6 liters/m(2), 11.6 liters/h/m(2), 0.42 h, and 8.1 h, respectively. The mean maximum plasma concentration at the MTD was 472.6 ng/ml (range: 249-577.8 ng/ml). Biological assays showed that the serum levels achieved could cause the characteristic cell cycle effects of this agent when serum was added to PC3 cells in culture, as well as increased histone acetylation in patient-derived peripheral blood mononuclear cells. The MTD of depsipeptide given on a day-1 and -5 schedule every 21 days is 17.8 mg/m(2). The DLTs are fatigue, nausea, vomiting, and transient thrombocytopenia and neutropenia. Whereas cardiac toxicity was anticipated based on preclinical data, there was no evidence of myocardial damage. However, reversible ECG changes with ST/T wave flattening were regularly observed. Biologically active serum concentrations were achieved, and 1 patient obtained a partial response. The recommended Phase II dose is 17.8 mg/m(2) administered on day 1 and 5 of a 21-day cycle.

Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors

Article

Full-text available

Sep 2002
NEW ENGL J MED

Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors. We conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor. We assessed antitumor response and the safety and tolerability of the drug. Pharmacokinetics were assessed in a subgroup of patients. A total of 147 patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53.7 percent) had a partial response, 41 patients (27.9 percent) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8 percent). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow-up of 24 weeks after the onset of response. Early resistance to imatinib was noted in 20 patients (13.6 percent). Therapy was well tolerated, although mild-to-moderate edema, diarrhea, and fatigue were common. Gastrointestinal or intraabdominal hemorrhage occurred in approximately 5 percent of patients. There were no significant differences in toxic effects or response between the two doses. Imatinib was well absorbed, with pharmacokinetics similar to those reported in patients with chronic myeloid leukemia. Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy.

Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade

Article

Full-text available

Sep 2002
SCIENCE

Constitutive Hedgehog (Hh) pathway activity is associated with initiation of neoplasia, but its role in the continued growth of established tumors is unclear. Here, we investigate the therapeutic efficacy of the Hh pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell–like character. This compound also caused regression of murine tumor allografts in vivo and induced rapid death of cells from freshly resected human medulloblastomas, but not from other brain tumors, thus establishing a specific role for Hh pathway activity in medulloblastoma growth.

Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571)

Article

Full-text available

Jan 2003

Imatinib mesylate, a selective inhibitor of the Abl tyrosine kinase, is effective as a single-agent therapy for chronic myelogenous leukemia. However, resistance has been reported, particularly in patients with advanced-stage disease. Mutations within the Abl kinase domain are a major cause of resistance, demonstrating that Bcr-Abl remains a critical drug target. Recently, a novel pyrido[2,3-d]pyrimidine derivative, PD180970, has been shown to potently inhibit Bcr-Abl and induce apoptosis in Bcr-Abl-expressing leukemic cells. We analyzed the inhibitory activity of PD180970 against Abl kinase domain mutations and cells expressing clinically relevant mutations. Our data indicate that PD180970 is active against several Bcr-Abl mutations that are resistant to imatinib and support the notion that developing additional Abl kinase inhibitors would be useful as a treatment strategy for chronic myelogenous leukemia.

Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis

Article

Full-text available

Jan 2003
CANCER CELL

To determine the impact of tumor progression on the reversibility of Neu-induced tumorigenesis, we have used the tetracycline regulatory system to conditionally express activated Neu in the mammary epithelium of transgenic mice. When induced with doxycycline, bitransgenic MMTV-rtTA/TetO-NeuNT mice develop multiple invasive mammary carcinomas, essentially all of which regress to a clinically undetectable state following transgene deinduction. This demonstrates that Neu-initiated tumorigenesis is reversible. Strikingly, extensive lung metastases arising from Neu-induced mammary tumors also rapidly and fully regress following the abrogation of Neu expression. However, despite the near universal dependence of both primary tumors and metastases on Neu transgene expression, most animals bearing fully regressed Neu-induced tumors ultimately develop recurrent tumors that have progressed to a Neu-independent state.

Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis

Article

Full-text available

Mar 2003
GENE DEV

Aberrant activation of Wnt signaling is oncogenic and has been implicated in a variety of human cancers. We have developed a doxycycline-inducible Wnt1 transgenic mouse model to determine the dependence of established mammary adenocarcinomas on continued Wnt signaling. Using this model we show that targeted down-regulation of the Wnt pathway results in the rapid disappearance of essentially all Wnt-initiated invasive primary tumors as well as pulmonary metastases. Tumor regression does not require p53 and occurs even in highly aneuploid tumors. However, despite the dependence of primary mammary tumors and metastases on continued Wnt signaling and the dispensability of p53 for tumor regression, we find that a substantial fraction of tumors progress to a Wnt-independent state and that p53 suppresses this process. Specifically, loss of one p53 allele dramatically facilitates the progression of mammary tumors to a Wnt1-independent state both by impairing the regression of primary tumors following doxycycline withdrawal and by promoting the recurrence of fully regressed tumors in the absence of doxycycline. Thus, although p53 itself is dispensable for tumor regression, it nevertheless plays a critical role in the suppression of tumor recurrence. Our findings demonstrate that although even advanced stages of epithelial malignancy remain dependent upon continued Wnt signaling for maintenance and growth, loss of p53 facilitates tumor escape and the acquisition of oncogene independence.

Bergers G, Benjamin LETumorigenesis and angiogenic switch. Nat Rev Cancer 3: 401-410

Article

Full-text available

Jul 2003
NAT REV CANCER

It has become evident that we cannot understand tumour growth without considering components of the stromal microenvironment, such as the vasculature. At the same time, the tumour phenotype determines the nature of the tumour vasculature. Much research is now devoted to determining the impact of angiogenesis on tumour development and progression, and the reciprocal influences of tumour products on the microvasculature. A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies-- not only for cancer treatment, but also for preventing recurrence.

A Randomized Trial of Bevacizumab, an Anti–Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer

Article

Full-text available

Jul 2003
NEW ENGL J MED

Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma. A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point. Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (hazard ratio, 2.55; P<0.001). There was a small difference, of borderline significance, between the time to progression of disease in the low-dose--antibody group and that in the placebo group (hazard ratio, 1.26; P=0.053). The probability of being progression-free for patients given high-dose antibody, low-dose--antibody, and placebo was 64 percent, 39 percent, and 20 percent, respectively, at four months and 30 percent, 14 percent, and 5 percent at eight months. At the last analysis, there were no significant differences in overall survival between groups (P>0.20 for all comparisons). Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer.

Biological Networks: The Tinkerer as an Engineer

Article

Full-text available

Oct 2003
SCIENCE

Uri Alon

This viewpoint comments on recent advances in understanding the design principles of biological networks. It highlights the surprising discovery of “good-engineering” principles in biochemical circuitry that evolved by random tinkering.

Frequency of Major Molecular Responses to Imatinib or Interferon Alfa plus Cytarabine in Newly Diagnosed Chronic Myeloid Leukemia

Article

Full-text available

Oct 2003
NEW ENGL J MED

In a randomized trial, 1106 patients with chronic myeloid leukemia (CML) in chronic phase were assigned to imatinib or interferon alfa plus cytarabine as initial therapy. We measured levels of BCR-ABL transcripts in the blood of all patients in this trial who had a complete cytogenetic remission. Levels of BCR-ABL transcripts were measured by a quantitative real-time polymerase-chain-reaction assay. Results were expressed relative to the median level of BCR-ABL transcripts in the blood of 30 patients with untreated CML in chronic phase. In patients who had a complete cytogenetic remission, levels of BCR-ABL transcripts after 12 months of treatment had fallen by at least 3 log in 57 percent of those in the imatinib group and 24 percent of those in the group given interferon plus cytarabine (P=0.003). On the basis of the rates of complete cytogenetic remission of 68 percent in the imatinib group and 7 percent in the group given interferon plus cytarabine at 12 months, an estimated 39 percent of all patients treated with imatinib but only 2 percent of all those given interferon plus cytarabine had a reduction in BCR-ABL transcript levels of at least 3 log (P<0.001). For patients who had a complete cytogenetic remission and a reduction in transcript levels of at least 3 log at 12 months, the probability of remaining progression-free was 100 percent at 24 months, as compared with 95 percent for such patients with a reduction of less than 3 log and 85 percent for patients who were not in complete cytogenetic remission at 12 months (P<0.001). The proportion of patients with CML who had a reduction in BCR-ABL transcript levels of at least 3 log by 12 months of therapy was far greater with imatinib treatment than with treatment with interferon plus cytarabine. Patients in the imatinib group with this degree of molecular response had a negligible risk of disease progression during the subsequent 12 months.

Transcriptional Regulation of the Melanoma Prognostic Marker Melastatin (TRPM1) by MITF in Melanocytes and Melanoma

Article

Full-text available

Feb 2004

Determining the metastatic potential of intermediate thickness lesions remains a major challenge in the management of melanoma. Clinical studies have demonstrated that expression of melastatin/TRPM1 strongly predicts nonmetastatic propensity and correlates with improved outcome, leading to a national cooperative prospective study, which is ongoing currently. Similarly, the melanocytic markers MLANA/MART1 and MITF also have been shown to lose relative expression during melanoma progression. Recent studies have revealed that MITF, an essential transcription factor for melanocyte development, directly regulates expression of MLANA. This prompted examination of whether MITF also might transcriptionally regulate TRPM1 expression. The TRPM1 promoter contains multiple MITF consensus binding elements that were seen by chromatin immunoprecipitation to be occupied by endogenous MITF within melanoma cells. Endogenous TRPM1 expression responded strongly to MITF up- or down-regulation, as did TRPM1 promoter-driven reporters. In addition, MITF and TRPM1 mRNA levels were correlated tightly across a series of human melanoma cell lines. Mice homozygously mutated in MITF showed a dramatic decrease in TRPM1 expression. Finally, the slope of TRPM1 induction by MITF was particularly steep compared with other MITF target genes, suggesting it is a sensitive indicator of MITF expression and correspondingly of melanocytic differentiation. These studies identify MITF as a major transcriptional regulator of TRPM1 and suggest that its prognostic value may be linked to MITF-mediated regulation of cellular differentiation.

Epigenetics in human disease and prospects for epigenetic therapy

Article

Full-text available

Jun 2004
NATURE

Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. Great potential lies in the development of 'epigenetic therapies'--several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.

Bevacizumab Plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer

Article

Full-text available

Jun 2004
NEW ENGL J MED

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.

Cetuximab Monotherapy and Cetuximab Plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer

Article

Full-text available

Aug 2004
NEW ENGL J MED

The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.

HSP90 and the chaperoning of cancer

Article

Jan 2005
NAT REV CANCER

Tumorigenesis and the angiogenic switch

Article

Jan 2003
NAT REV CANCER

Phase II Multicenter Study of the Antiepidermal Growth Factor Receptor Monoclonal Antibody Cetuximab in Combination With Platinum-Based Chemotherapy in Patients With Platinum-Refractory Metastatic and/or Recurrent Squamous Cell Carcinoma of the Head and Neck

Article

Jul 2005

José Baselga

Purpose To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m² followed by subsequent weekly doses of 250 mg/m²) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study. Results The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adverse events were skin reactions, particularly an acne-like rash. Conclusion The combination of cetuximab and platinum chemotherapy is an active and well-tolerated approach to the treatment of this poor-prognosis patient population with platinum-refractory recurrent or metastatic SCCHN for whom there are no recommended standard therapeutic options.

Apoptosis. Its significance in cancer and cancer Therapy

Article

Apr 1994
CANCER-AM CANCER SOC

Apoptosis is a distinct mode of cell death that is responsible for deletion of cells in normal tissues; it also occurs in specific pathologic contexts. Morphologically, it involves rapid condensation and budding of the cell, with the formation of membrane-enclosed apoptotic bodies containing well-preserved organelles, which are phagocytosed and digested by nearby resident cells. There is no associated inflammation. A characteristic biochemical feature of the process is double-strand cleavage of nuclear DNA at the linker regions between nucleosomes leading to the production of oligonucleosomal fragments. In many, although not all of the circumstances in which apoptosis occurs, it is suppressed by inhibitors of messenger RNA and protein synthesis. Apoptosis occurs spontaneously in malignant tumors, often markedly retarding their growth, and it is increased in tumors responding to irradiation, cytotoxic chemotherapy, heating and hormone ablation. However, much of the current interest in the process stems from the discovery that it can be regulated by certain proto-oncogenes and the p53 tumor suppressor gene. Thus, c-myc expression has been shown to be involved in the initiation of apoptosis in some situations, and bcl-2 has emerged as a new type of proto-oncogene that inhibits apoptosis, rather than stimulating mitosis. In p53-negative tumor-derived cell lines transfected with wild-type p53, induction of the gene has, in rare cases, been found to cause extensive apoptosis, instead of growth arrest. Finally, the demonstration that antibodies against a cell-surface protein designated APO-1 or Fas can enhance apoptosis in some human lymphoid cell lines may have therapeutic implications.

Targeted agents for the treatment of advanced renal cell carcinoma

Article

Dec 2005
CANCER-AM CANCER SOC

Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, the elucidation of the molecular mechanisms underlying RCC development has led to the identification of promising targets for novel therapeutic agents. The involvement of the Von Hippel–Lindau protein pathway in clear cell RCC suggests that downstream targets of this pathway, namely, signaling through vascular endothelial growth factor (VEGF) in endothelial cells, platelet-derived growth factor (PDGF) in endothelial cells and pericytes, and the epidermal growth factor receptor (EGFR) pathway in tumor cells are all reasonable and rational therapeutic targets. A number of agents are in development that target VEGF (bevacizumab, a recombinant, humanized monoclonal antibody) or its receptor, VEGFR (PTK787, SU011248, and BAY 43-9006, all of which are small molecule inhibitors). Agents targeting EGFR also are being investigated clinically (gefitinib, cetuximab, erlotinib, and ABX-EGF). The Raf/MEK/ERK pathway is an important downstream convergence point for signaling through VEGFR, platelet-derived growth factor receptor (PDGFR), and EGFR (all have receptor tyrosine kinase activity) and also has important antiapoptotic effects, thereby providing an attractive target for intervention. In addition to inhibiting VEGFR and PDGFR-mediated angiogenic pathways, BAY 43-9006 has been shown to inhibit the Raf/MEK/ERK pathway at the level of Raf kinase. MEK-directed therapeutic approaches are also in development. Given that multiple molecular pathways are implicated in tumor cell growth, antitumor activity may be increased by using individual agents that target multiple pathways, or by combining different agents to allow vertical or horizontal inhibition of relevant pathways. Cancer 2005. © 2005 American Cancer Society.

Antisense to cyclin D1 inhibits growth and reverts the transformed phenotype of human esophageal cancer cells

Article

Sep 1995
ONCOGENE

The cyclin D1 gene is amplified and overexpressed in a significant fraction of human esophageal tumors, and several other types of human cancer, but the functional significance of this overexpression has not been established. To further address the roles of cyclin D1 in growth control and tumorigenesis, we have overexpressed an antisense cyclin D1 cDNA construct, either constitutively or inducibly, in the HCE7 human esophageal cancer cell line in which cyclin D1 is amplified and expressed at high levels. The expression of antisense cyclin D1 led to decreased expression of cyclin D1 at both mRNA and protein levels, and this was associated with a marked inhibition of cell proliferation. Antisense cyclin D1 expressing cells displayed a decreased plating efficiency, increased doubling time, decreased saturation density, increased cell size, decreased cyclin D1-associated in vitro kinase activity, decreased anchorage-independent growth, and a loss of tumorigenicity in nude mice. These findings provide direct evidence that the overexpression of cyclin D1 in certain tumor cells contributes to their abnormal growth and tumorigenicity. The ability to revert the transformed phenotype of these cells with antisense cyclin D1 suggests that cyclin D1 may be a useful target in cancer therapy.

Suppression of Ki-ras p21 levels leading to growth inhibition of pancreatic cancer cell lines with Ki-ras mutation but not those without Ki-ras mutation

Article

Nov 1997

Ki-ras point mutation characteristically occurs frequently in human pancreatic cancer. To clarify the effect of antisense Ki-ras RNA on various pancreatic cancer cell lines, a plasmid expressing an antisense Ki-ras gene fragment (AS-K-ras-LNSX) was transduced into seven human pancreatic cancer cell lines (AsPC-1, MIA PaCa-2, PANC-1, PSN-1, BxPC-3, Hs 700T, and Hs 766T) by liposome-mediated transfection. Western blot analysis showed that transfection of AS-K-ras-LNSX led to a significant reduction in the amounts of Ki-ras p21 protein in all the pancreatic cancer cell lines except BxPC-3. The growth of pancreatic cancer cell lines having Ki-ras point mutations (AsPC-1, MIA PaCa-2, PANC-1, and PSN-1) was suppressed after transduction of AS-K-ras-LNSX, whereas the effect of the antisense construct on the growth was not significant in cell lines with a wild-type Ki-ras gene (BxPC-3, Hs 700T, and Hs 766T). These results suggest that the pancreatic cancer cells with activated Ki-ras depend heavily on a Ki-ras p21-mediated growth signal pathway for their growth because they were far more susceptible to the suppression of the Ki-ras p21 protein than the cells with wild-type Ki-ras. The remarkably increased dependence of the cancer-cell growth circuitry on one or a few crucial regulatory molecules may thus be a common feature of the cancer cells and implies a novel rationale for the targeting of cancer therapy.

Essential role for oncogenic Ras in tumour maintenance

Article

Aug 1999

Advanced malignancy in tumours represents the phenotypic endpoint of successive genetic lesions that affect the function and regulation of oncogenes and tumour-suppressor genes. The established tumour is maintained through complex and poorly understood host-tumour interactions that guide processes such as angiogenesis and immune sequestration. The many different genetic alterations that accompany tumour genesis raise questions as to whether experimental cancer-promoting mutations remain relevant during tumour maintenance. Here we show that melanoma genesis and maintenance are strictly dependent upon expression of H-RasV12G in a doxycycline-inducible H-Ras12G mouse melanoma model null for the tumour suppressor INK4a. Withdrawal of doxycycline and H-RasV12G down-regulation resulted in clinical and histological regression of primary and explanted tumours. The initial stages of regression involved marked apoptosis in the tumour cells and host-derived endothelial cells. Although the regulation of vascular endothelial growth factor (VEGF) was found to be Ras-dependent in vitro, the failure of persistent endogenous and enforced VEGF expression to sustain tumour viability indicates that the tumour-maintaining actions of activated Ras extend beyond the regulation of VEGF expression in vivo. Our results provide genetic evidence that H-RasV12G is important in both the genesis and maintenance of solid tumours.

Felsher DW, Bishop JMReversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 4: 199-207

Article

Sep 1999
MOL CELL

The targeted repair of mutant protooncogenes or the inactivation of their gene products may be a specific and effective therapy for human neoplasia. To examine this possibility, we have used the tetracycline regulatory system to generate transgenic mice that conditionally express the MYC protooncogene in hematopoietic cells. Sustained expression of the MYC transgene culminated in the formation of malignant T cell lymphomas and acute myleoid leukemias. The subsequent inactivation of the transgene caused regression of established tumors. Tumor regression was associated with rapid proliferative arrest, differentiation and apoptosis of tumor cells, and resumption of normal host hematopoiesis. We conclude that even though tumorigenesis is a multistep process, remediation of a single genetic lesion may be sufficient to reverse malignancy.

Antisense cyclin D1 induces apoptosis and tumor shrinkage in human squamous carcinomas

Article

Nov 1999

Cyclin D1 plays an essential regulatory role in the G1 phase of the cell cycle. The cyclin D1 gene is amplified in 20-50% of squamous cell carcinomas (SCCs), and the protein is overexpressed in up to 80% of SCCs. Our hypothesis was that gene transduction of antisense (AS) cyclin D1 in human SCCs in vivo would result in tumor reduction. A cyclin D1 cDNA was inserted into an E1/E3-deficient serotype 5 adenovirus (AS cyclin D1) in an AS orientation using homologous recombination. AS cyclin D1 transduction suppressed cyclin D1 protein expression in both cultured cells and tumors. AS cyclin D1 significantly inhibited cell proliferation by both [3H]thymidine incorporation in six SCC cell lines (P = 0.01-0.001) and the conversion of tetrazolium salt to formazan in four SCC cell lines (P = 0.01-0.004). Apoptosis detected in >25% of cells in each cell line 48 h after AS cyclin D1 transduction paralleled the reduction in cyclin D1 protein. Preformed SCCs transduced with AS cyclin D1 were significantly inhibited (P = 0.002-0.005), and apoptosis was prominent in the AS cyclin D1-treated tumors, but not in tumors treated with the control vector. These data extend prior in vitro and ex vivo results and indicate that AS cyclin D1 suppresses SCC growth both in vitro and in vivo through suppression of cyclin D1 protein expression, leading to cellular apoptosis. Our findings suggest that cyclin D1 may have a role in cell survival and that cyclin D1 AS therapy may be useful as an adjunct to standard treatment for SCC.

Disorders in cell circuitry during multistage carcinogenesis: The role of homeostasis

Article

Jun 2000

I.B. Weinstein

The multistage process of carcinogenesis involves the progressive acquisition of mutations, and epigenetic abnormalities in the expression, of multiple genes that have highly diverse functions. An important group of these genes are involved in cell cycle control. Thus, cyclin D1 is frequently overexpressed in a varety of human cancers. Cylin D1 plays a critical role in carcinogenesis because (i) overexpression enhances cell transformation and tumorigenesis, and enhances the amplification of other genes, and (ii) an antisense cyclin D1 cDNA reverts the malignant phenotype of carcinoma cells. Therefore, cyclin D1 may be a useful biomarker in molecular epidemiology studies, and inhibitors of its function may be useful in both cancer chemoprevention and therapy. We discovered a paradoxical increase in the cell cycle inhibitors protein p27(Kip1) in a subset of human cancers, and obtained evidence for homeostatic feedback loops between cyclins D1 or E and p27(Kip1). Furthermore, derivatives of HT29 colon cancer cells with increased levels of p27(Kip1) showed increased sensitivity to induction of differentiation. This may explain why decreased p27(Kip1) in a subset of human cancers is associated with a high grade (poorly differentiated) histology and poor prognosis. Agents that increase cellular levels of p27(Kip1) may, therefore, also be useful in cancer therapy. Using an antisense Rb oligonucleotide we obtained evidence that the paradoxical increase in pRb often seen in human colon cancers protects these cells from growth inhibition and apopotosis. On the basis of these, and other findings, we hypothesize that homeostatic feedback mechanisms play a critical role in multistage carcinogenesis. Furthermore, because of their bizarre circuitry, cancer cells suffer from 'gene addiction' and 'gene hypersensitivity' disorders that might be exploited in both cancer prevention and chemotherapy.

Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification

Article

Sep 2001

Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, we find that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined. In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI-571 resistance in a reconstitution experiment. In three patients, resistance was associated with progressiveBCR-ABL gene amplification. These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI-571 resistance.

Mechanism of action of anti-HER2 monoclonal antibodies

Article

Feb 2001

The search for new methods of treating cancer, combined with advances in our understanding of carcinogenesis, molecular biology and technology, has resulted in the development of novel biologic agents with proven clinical efficacy. One such agent is trastuzumab (Herceptin), a humanized monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2). HER2 is a member of a family of receptors that interact with each other and various ligands to stimulate various intracellular signal transduction pathways involved in cell growth control. HER2 is overexpressed in 20%-30% of women with breast cancer and is associated with aggressive tumor characteristics and poor prognosis. Trastuzumab is the first humanized monoclonal antibody to be approved for therapeutic use and the first oncogene-targeted treatment with proven survival benefit in women with HER2-positive metastatic breast cancer. However, its mechanism of action has not been fully characterized and appears to be complex. This paper reviews current knowledge of the mechanism of action of trastuzumab, including HER2 protein downregulation, prevention of HER2-containing heterodimer formation, initiation of G1 arrest and induction of p27, prevention of HER2 cleavage, inhibition of angiogenesis, and induction of immune mechanisms. The significance of these mechanisms for selection of concomitant chemotherapy is also considered.

Linking molecular therapeutics to molecular diagnostics: Inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo

Article

Sep 2001

Molecular therapeutics, targeting the underlying defects leading to cancer initiation and progression, are the “holy grail” of cancer research, translation, and therapy. This quest has taken a major leap forward with the demonstration that STI571 (Gleevec) induces clinical remissions in over 90% and molecular remissions in 10–20% of patients with IFN-refractory chronic phase chronic myelogenous leukemia (CML). The efficacy of STI571 in CML has been shown to be caused by the requirement of the bcr/abl fusion protein, unique to CML, for its initiation and progression, requiring molecular diagnostics to identify sensitive patients. A plethora of molecular therapeutics targeting signal transduction pathways are under evaluation. Despite the presence of the target in normal cells, the drugs have, in general, been remarkably nontoxic as compared with conventional chemotherapy or radiation therapy (see Fig. 1). As expected, these agents exhibit little, if any, activity in tumors where the target is not amplified or activated. Thus individualization of therapy driven by effective molecular diagnostic approaches to determine the status of the targets in patients' cancers is as essential a component of a molecular therapeutics program as is the identification and validation of new targets or the development of novel targeted drugs.

Cancer gene therapy: Fringe or cutting edge?

Article

Dec 2001
NAT REV CANCER

Frank McCormick

Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally--a challenge that has been successfully addressed.

Suppression of Myc-Induced Apoptosis in ?? Cells Exposes Multiple Oncogenic Properties of Myc and Triggers Carcinogenic Progression

Article

Jun 2002
CELL

To explore the role of c-Myc in carcinogenesis, we have developed a reversible transgenic model of pancreatic beta cell oncogenesis using a switchable form of the c-Myc protein. Activation of c-Myc in adult, mature beta cells induces uniform beta cell proliferation but is accompanied by overwhelming apoptosis that rapidly erodes beta cell mass. Thus, the oncogenic potential of c-Myc in beta cells is masked by apoptosis. Upon suppression of c-Myc-induced beta cell apoptosis by coexpression of Bcl-x(L), c-Myc triggers rapid and uniform progression into angiogenic, invasive tumors. Subsequent c-Myc deactivation induces rapid regression associated with vascular degeneration and beta cell apoptosis. Our data indicate that highly complex neoplastic lesions can be both induced and maintained in vivo by a simple combination of two interlocking molecular lesions.

Sustained Loss of a Neoplastic Phenotype by Brief Inactivation of MYC

Article

Aug 2002
SCIENCE

Pharmacological inactivation of oncogenes is being investigated as a possible therapeutic strategy for cancer. One potential drawback is that cessation of such therapy may allow reactivation of the oncogene and tumor regrowth. We used a conditional transgenic mouse model for MYC-induced tumorigenesis to demonstrate that brief inactivation of MYC results in the sustained regression of tumors and the differentiation of osteogenic sarcoma cells into mature osteocytes. Subsequent reactivation of MYC did not restore the cells' malignant properties but instead induced apoptosis. Thus, brief MYC inactivation appears to cause epigenetic changes in tumor cells that render them insensitive to MYC-induced tumorigenesis. These results raise the possibility that transient inactivation of MYC may be an effective therapy for certain cancers.

CANCER: Enhanced: Addiction to Oncogenes--the Achilles Heal of Cancer

Article

Aug 2002
SCIENCE

I. Bernard Weinstein

A series of recent studies are providing tantalizing hints of new therapeutic approaches for combating cancer. In his Perspective, [Weinstein][1] discusses new work ([ Jain et al .][2]) demonstrating that even brief inactivation of an oncogene can permanently reverse the malignant phenotype of some types of tumor. [1]: http://www.sciencemag.org/cgi/content/full/297/5578/63 [2]: http://www.sciencemag.org/cgi/content/short/297/5578/102

Brummelkamp TR, Bernards R, Agami R.. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2: 243-247

Article

Oct 2002
CANCER CELL

Most human tumors harbor multiple genetic alterations, including dominant mutant oncogenes. It is often not clear which of these oncogenes are continuously required and which, when inactivated, may inhibit tumorigenesis. Recently, we developed a vector that mediates suppression of gene expression through RNA interference. Here, we use a retroviral version of this vector to specifically and stably inhibit expression of only the oncogenic K-RAS(V12) allele in human tumor cells. Loss of expression of K-RAS(V12) leads to loss of anchorage-independent growth and tumorigenicity. These results indicate that viral delivery of small interfering RNAs can be used for tumor-specific gene therapy to reverse the oncogenic phenotype of cancer cells.

Proteasome Inhibitors as anticancer drugs

Article

Dec 2002

Julian Adams

The targeted degradation of key regulatory proteins is an essential element of cell cycle control. The proteasome plays a central role in the degradation of such proteins and has therefore become an important therapeutic target for diseases involving cell proliferation, notably cancer. This review summarizes numerous studies demonstrating that proteasome inhibition induces apoptosis and sensitizes cancer cells to traditional tumoricidal agents both and The potent and selective proteasome inhibitor, PS-341, is particularly promising from a therapeutic perspective, and it is the only such inhibitor that has progressed to clinical trials. Preliminary data indicate that the drug is well tolerated by patients with cancer, and further trials are underway to assess the safety and efficacy of proteasome inhibition in hematologic and solid tumors, both as a monotherapy and in combination with other chemotherapeutics.

Small interfering RNAs directed against ??-Catenin inhibit the in vitro and in vivo growth of colon cancer cells

Article

May 2003

The beta-catenin and APC genes are key components of the Wnt signaling pathway. Mutation of these genes results in increased levels of the beta-catenin protein, which is associated with enhanced cellular proliferation and the development of both colon polyps and colon cancer. Recently, a technique known as RNA interference has been successfully adapted to mammalian cells so that it is now possible to specifically decrease the expression of cellular genes after transfection of annealed small interfering 21-mer RNAs. In the current study, we used small interfering RNA (siRNA) directed against beta-catenin to determine the effects of decreasing the high constitutive levels of this protein in colon cancer cell lines with mutations in either beta-catenin or APC. Our studies demonstrate that siRNA directed against beta-catenin markedly decreased beta-catenin-dependent gene expression and inhibited cellular proliferation as reflected in the reduced growth of these colon cancer cells both in soft agar and in nude mice. These results indicate that siRNA can target specific factors whose expression is altered in malignancy and may have the potential as a therapeutic modality to treat human cancer.

Molecular Networks: The Top-Down View

Article

Oct 2003
SCIENCE

Dennis Bray

Network theory can give a useful overview of how a biological system works. But to make testable predictions, we need the details.

Engineering Complex Systems

Article

Feb 2004
NATURE

Julio M. Ottino

Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and how science impacts upon all aspects of society and life.

A resource for large-scale RNA-interference-based screens in mammals

Article

Apr 2004
NATURE

Gene silencing by RNA interference (RNAi) in mammalian cells using small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) has become a valuable genetic tool. Here, we report the construction and application of a shRNA expression library targeting 9,610 human and 5,563 mouse genes. This library is presently composed of about 28,000 sequence-verified shRNA expression cassettes contained within multi-functional vectors, which permit shRNA cassettes to be packaged in retroviruses, tracked in mixed cell populations by means of DNA 'bar codes', and shuttled to customized vectors by bacterial mating. In order to validate the library, we used a genetic screen designed to report defects in human proteasome function. Our results suggest that our large-scale RNAi library can be used in specific, genetic applications in mammals, and will become a valuable resource for gene analysis and discovery.

Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib

Article

Jun 2004
NEW ENGL J MED

Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

The development of proteasome inhibitors as anticancer drugs

Article

Jun 2004
CANCER CELL

Julian Adams

The ubiquitin-proteasome pathway plays a central role in the targeted destruction of cellular proteins, including cell cycle regulatory proteins. Because these pathways are critical for the proliferation and survival of all cells, and in particular cancerous cells, proteasome inhibition is a potentially attractive anticancer therapy. Based on encouraging cytotoxic activity, bortezomib was the first proteasome inhibitor to be evaluated in clinical trials. Efficacy and safety results from a phase 2 clinical trial contributed to approval of bortezomib for use in patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies and have demonstrated disease progression on their last therapy.

Sordella R, Bell DW, Haber DA, Settleman JGefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305: 1163-1167

Article

Sep 2004
SCIENCE

Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. We report that these mutant EGFRs selectively activate Akt and signal transduction and activator of transcription (STAT) signaling pathways, which promote cell survival, but have no effect on extracellular signal–regulated kinase signaling, which induces proliferation. NSCLC cells expressing mutant EGFRs underwent extensive apoptosis after small interfering RNA–mediated knockdown of the mutant EGFR or treatment with pharmacological inhibitors of Akt and STAT signaling and were relatively resistant to apoptosis induced by conventional chemotherapeutic drugs. Thus, mutant EGFRs selectively transduce survival signals on which NSCLCs become dependent; inhibition of those signals by gefitinib may contribute to the drug's efficacy.

Mechanisms of Disease: Oncogene addiction - A rationale for molecular targeting in cancer therapy

Abstract

No full-text available

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