OncoBriefs: Delayed Tx for Prostate Ca, New Antiandrogen

“Prostate cancer mortality has declined by more than 60% compared with historical data for a cohort of conservatively managed patients followed for more than 20 years, a retrospective analysis showed.

“The findings will be reported in detail at the 50th anniversary meeting of the American Society of Clinical Oncology, which begins here May 30. Other ASCO-related prostate cancer data included in this edition of OncoBriefs come from studies of physical activity to counteract adverse effects of androgen-deprivation therapy (ADT) and preliminary clinical results from a trial of an investigational second-generation androgen inhibitor.”

Editor’s note: This article gives a good overview of some important prostate cancer news that will be discussed this weekend at the American Society of Clinical Oncology (ASCO) Annual Meeting. In addition to lower mortality and the benefits of physical activity for men treated with ADT, the article discusses promising results for a drug called ARN-509, which may benefit patients with metastatic castration-resistant prostate cancer.

An F876L Mutation in Androgen Receptor Confers Genetic and Phenotypic Resistance to MDV3100 (Enzalutamide)

“Castration resistant prostate cancer (CRPC) is the most aggressive, incurable form of prostate cancer. MDV3100 (enzalutamide), an antagonist of the androgen receptor (AR), was approved for clinical use in men with metastatic CRPC. Although this compound showed clinical efficacy, many initial responders later developed resistance. To uncover relevant resistant mechanisms, we developed a model of spontaneous resistance to MDV3100 in LNCaP prostate cancer cells. Detailed characterization revealed that emergence of F876L mutation in AR correlated with blunted AR response to MDV3100 and sustained proliferation during treatment. Functional studies confirmed that AR-F876L confers an antagonist-to-agonist switch that drives phenotypic resistance. Lastly, treatment with distinct anti-androgens or CDK4/6 inhibitors effectively antagonized AR-F876L function. Together, these findings suggest that emergence of F876L may 1) serve as a novel biomarker for prediction of drug sensitivity, 2) predict a “withdrawal” response to MDV3100, and 3) be suitably targeted with other anti-androgens or CDK4/6 inhibitors.”

A Clinically Relevant Androgen Receptor Mutation Confers Resistance to 2nd Generation Anti-Androgens Enzalutamide and ARN-509

“Despite the impressive clinical activity of 2nd generation anti-androgens enzalutamide and ARN-509 in prostate cancer patients, acquired resistance invariably emerges. To identify the molecular mechanisms underlying acquired resistance, we developed and characterized cell lines resistant to ARN-509 and enzalutamide. In a subset of cell lines, ARN-509 and enzalutamide exhibit agonist activity, due to a missense mutation (F876L) in the ligand binding domain of the androgen receptor (AR). AR F876L is sufficient to confer resistance to ARN-509 and enzalutamide in in vitro and in vivo models of CRPC.”

Identification of Antiandrogen Resistance Mutation Leads to Design of Molecules That Could Overcome Resistance

Researchers recently identified a genetic mutation that results in resistance to the drug enzalutamide (Xtandi) and to other second-generation antiandrogen receptor drugs. The discovery has already led to the design of new compounds that could overcome this type of resistance in prostate cancer patients. Those compounds are in preclinical studies. Continue reading…

Amplification of a Stat5 Gene Produces Excess Oncogenic Protein that Drives Prostate Cancer Spread

“Scientists have solved the mystery of why a substantial percentage of castrate-resistant metastatic prostate cancer cells contain abnormally high levels of the pro-growth protein Stat5…”

Evolving Landscape and Novel Treatments in Metastatic Castrate-Resistant Prostate Cancer

Treatment options for castrate-resistant prostate cancer (CRPC) have advanced in recent years and significantly improved the outlook for patients with this aggressive and lethal disease. Further understanding of the biology of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor (AR) directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC…”

Overcoming mutation-based resistance to antiandrogens with rational drug design

The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist…”

Estrogen Skin Patch May Be an Effective Treatment for Prostate Cancer

A study published in the Lancet Oncology suggests that estrogen skin patches may be an effective way to treat prostate cancer. Estrogen works by decreasing testosterone levels in the same way as antiandrogen therapy, but without many of the medical risks associated with antiandrogen therapy. Larger trials are planned to study their long term effectiveness and safety.

Research paper: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70025-1/fulltext


Autophagy Can Modulate Responses to Treatments in Castration-Resistant Prostate Cancer Patients

Dr. Christopher P. Evans examines how autophagy, a relatively recently appreciated mechanism in cell and tumor biology, can regulate responses to prostate cancer treatments including chemotherapy and anti-androgen therapy in castrate-resistant prostate cancer.