“By assessing plasma androgen receptor (AR) gene status assessment with multiplex droplet digital PCR (ddPCR), European researchers could predict which patients with castration-resistant prostate cancer (CRPC) were most likely to have poorer outcomes while undergoing targeted therapy, according to results from the PREMIER trial published in the Annals of Oncology.
“Researchers said there was a ‘significant association’ for AR gain and poorer overall survival (OS) for both chemotherapy-naïve patients (HR, 3.98; 95% CI, 1.75-9.10; P <.001) and patients previously treated with docetaxel (HR, 3.81; 95% CI, 2.28-6.37; P <.001). AR gain was also associated with poorer OS for chemotherapy-naïve patients treated with enzalutamide (Xtandi) or abiraterone acetate (Zytiga; HR, 2.18; 95% CI, 1.08-4.39; P = .03) and for patients previously treated with docetaxel (HR, 1.95; 95% CI, 1.23-3.11; P = .01).”
“For decades, the standard of care for men with advanced prostate cancer has been the depletion or inhibition of androgens. While androgen-deprivation therapy (ADT) often results in temporary tumor regression or symptom relief in some patients, disease progression ultimately occurs over time. For patients with metastatic disease, the median overall survival (OS), until very recently, had been less than 2 years after chemotherapy.
“While tumor progression with ADT was previously believed to be hormone-refractory or androgen-independent, a large body of evidence supports that metastatic castration-resistant prostate cancer (mCRPC) is commonly driven by elevated steroid synthesis, increased expression or splice variants of the androgen receptor (AR), or AR ligand promiscuity, indicating the ongoing need for targeted androgen therapies.”
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“Results of a multicenter phase 1 clinical trial presented today at the 2015 San Antonio Breast Cancer Symposium show that the anti-androgen agent enzalutamide is active and well-tolerated alone and with fulvestrant in patients with advanced breast cancer. The study takes another important step toward larger clinical trials targeting androgen receptors in breast cancer.
” ‘We’ve known for years that prostate cancer is driven by androgens and now it’s increasingly clear that androgens and androgen receptors can influence many breast cancers as well. AR is actually even more prevalent in breast cancer than estrogen or progesterone receptors. Targeting androgen receptors in breast cancer gives us a new way to attack the disease,’ says Jennifer Richer, PhD, investigator at the University of Colorado Cancer Center. Results represent collaboration with CU Cancer Center clinical collaborator Anthony Elias, MD, Memorial Sloan Kettering, Medivation, Inc. and Astellas Pharma Global Development.”
“The study is also a proof of principle that tests for cancer DNA in the bloodstream can be used to detect drug resistance mutations – allowing patients who will not benefit from one drug to be given an alternative treatment instead.
“Researchers at The Institute of Cancer Research, London, the Royal Marsden NHS Foundation Trust, and the University of Trento, Italy, analysed 274 blood samples from 97 patients using state-of-the-art DNA sequencing techniques.
“They found that mutations in a gene called the androgen receptor (AR) predicted resistance to the prostate cancer drug abiraterone, and that patients with these mutations had poorer survival.”
For men with advanced prostate cancer, androgen deprivation therapy (ADT) is usually the initial treatment of choice. ADT slows the growth of prostate tumors and can even make them shrink. But unfortunately, the results of ADT are short-lived; tumors can develop resistance to ADT and grow back, sometimes stronger than before. Scientists are hard at work to figure out the underlying mechanisms of ADT resistance and how to bypass it. Continue reading…
The vast majority of high-risk prostate cancer cases are caused by abnormally high activity of a protein called the androgen receptor. Present in many prostate cells, androgen receptors detect androgen hormones (including testosterone), and in response, turn on or off genes. Genes that are regulated by androgen hormones are critical for the development of the prostate and maintenance of its function. But when the androgen receptor is overly active, which can occur via several different processes in the aging prostate, it can activate genes that can lead to uncontrolled proliferation of prostate cells. This contributes to the development of aggressive prostate cancer. Continue reading…
Nyquista MD, Lia Y, Hwangc TH, Manlovea LS, et al. PNAS. Oct 7, 2013.
“The androgen receptor (AR) is a master regulator in cells of prostatic origin, including prostate cancer. How AR activity can persist in tumors that are resistant to second-generation AR-targeted therapies remains unknown. This study describes the discovery of AR gene rearrangements in clinical prostate cancer tissues, and the use of genome engineering in prostate cancer cells with transcription activator-like effector nucleases to functionally classify these gene rearrangements as drivers of resistance. This knowledge is expected to lead to better patient management and enable the development of more effective therapies for advanced prostate cancer.”
“The androgen receptor (AR), a member of the nuclear receptor family, is a transcription factor involved in prostate cell growth, homeostasis and transformation. AR is a key protein in growth and development of both normal and malignant prostate making it a common therapeutic target in prostate cancer (PCa). AR is regulated by an interplay of multiple post-translational modifications including ubiquitination. We and others have shown that the AR is ubiquitinated by a number of E3 ubiquitin ligases, including MDM2, CHIP and NEDD4 which can result in its proteosomal degradation or enhanced transcriptional activity. As ubiquitination of AR causes a change in AR activity or stability and impacts both survival and growth of PCa cells, deubiquitination of these sites has an equally important role. Hence deubiquitinating enzymes (DUBs) could offer novel therapeutic targets. We performed an siRNA screen to identify DUBs that regulate AR, in that screen ubiquitin specific protease 12 (Usp12) was identified as a novel positive regulator of AR. Usp12 is a poorly characterised protein with few known functions and requires the interaction with two cofactors, Uaf-1 and WDR20, for its enzymatic activity. In this report we demonstrate that Usp12, in complex with Uaf-1 and WDR20, deubiquitinates the AR to enhance receptor stability and transcriptional activity. Our data shows that Usp12 acts in a pro-proliferative manner by stabilising AR and enhancing its cellular function.”
Mygatt JG, Singhal A, Sukumar G, Dalgard CL, Kaleeba JAR. Cancer Research. Sep 15, 2013.
“Mechanisms underlying progression to androgen-independent prostate cancer following radical ablation therapy remain poorly defined. Although intraprostatic infections have been highlighted as potential cofactors, pathogen influences on pathways that support tumor regrowth are not known. To explore this provocative concept, we derived androgen-sensitive and -insensitive prostate epithelial cells persistently infected with human herpesvirus 8 (HHV-8), an oncogenic herpesvirus that has been detected in normal prostate epithelium, prostate adenocarcinoma, and biologic fluids of patients with prostate cancer, to explore its effects on transition to hormone-refractory disease. Strikingly, we found that HHV-8 infection of androgen-sensitive prostate cancer cells conferred the capacity for androgen-independent growth. This effect was associated with altered expression and transcriptional activity of the androgen receptor (AR). However, HHV-8 infection bypassed AR signaling by promoting enhancer of zeste homolog 2 (EZH2)–mediated epigenetic silencing of tumor-suppressor genes, including MSMB andDAB2IP that are often inactivated in advanced disease. Furthermore, we found that HHV-8 triggered epithelial-to-mesenchymal transition. Although HHV-8 has not been linked etiologically to prostate cancer, virologic outcomes revealed by our study provide mechanistic insight into how intraprostatic infections could constitute risk for progression to androgen-independent metastatic disease where EZH2 has been implicated. Taken together, our findings prompt further evaluations of the relationship between HHV-8 infections and risk of advanced prostate cancer.”