Monday, September 8, 2014

AR-V7 Identifies Patients Unlikely to Respond to Common Therapy for Advanced Prostate Cancer


Prostate cancer is driven by male hormones (otherwise known as androgens) like testosterone. In men with advanced prostate cancer, androgen deprivation therapy (ADT), or therapies that block androgens from acting on prostate cancer cells, can slow or stop the progression of the cancer. Unfortunately, prostate cancer cells will eventually survive and grow despite standard, first-line ADT – a state called castration-resistant prostate cancer (CRPC). For these men, treatments that further suppress the generation of androgens or block the androgen receptor are the next step. Abiraterone is a medication that inhibits important enzymes in the synthesis of androgens and enzalutamide blocks androgens from acting on the receptor on prostate cancer cells. These medications extend the lives of approximately 80% of the men who take them, however 20% will have little or no response.

Researchers at Johns Hopkins' Kimmel Cancer Center and Brady Urological Institute may have discovered why. These findings were published in the most recent version of the NEJM (New England Journal of Medicine) and demonstrate that prostate cancer patients whose tumors contain a shortened receptor called AR-V7 are less likely to respond to abiraterone or enzalutamide. AR-V7 is a shortened form of the androgen receptor that lacks a binding spot targeted by enzalutamide and abiraterone. With no binding spot for the two drugs, AR-V7 is free to manipulate prostate cancer cells' genetic material, which makes the cancer cells grow and spread. A total of 62 patients, 31 patients taking each medication, were studied by looking for AR-V7 in circulating tumor cells (CTCs) from blood samples.

Waterfall Plots of Best Prostate-Specific
Antigen (PSA) Responses According to
AR-V7 Status.  From NEJM.
Of the 31 patients taking enzalutamide:
  • 39% were AR-V7-positive, and in these patients:
    • None (0%) had a PSA reduction, compared to 53% of patients who were AR-V7-negative (P=0.004)
    • PSA-progression-free survival was shorter (1.4 months vs. 6.0 months, P<0.001)
    • Survival was shorter (5.5 months vs. not reached, P=0.002)
Of the 31 patients taking abiraterone:
  • 19% were AR-V7-positive, and in these patients:
    • None (0%) had a PSA reduction, compared to 68% of patients who were AR-V7-negative (P=0.004)
    • PSA-progression-free survival was shorter (1.3 months vs. not reached, P<0.001)
    • Survival was shorter (10.6 months vs. not reached, P=0.006)
Jun Luo, PhD
"In this study, we've connected AR-V7 detection with resistance to two popular drugs for prostate cancer, and we've done it in a non-invasive way," says Jun Luo, Ph.D., Associate Professor of Urology at the Brady Urological Institute at Johns Hopkins first identified AR-V7 in 2007. "We hope this study will motivate scientists and clinicians to conduct additional studies on AR-V7 and to develop effective therapies to overcome resistance."

"Until now, we haven't been able to predict which patients will not respond to these therapies. If our results are confirmed by other researchers, a simple blood test could use AR-V7 as a biomarker to predict enzalutamide and abiraterone resistance, and let us direct patients who test positive for AR-V7 toward other types of therapy sooner, saving time and money while avoiding futile therapy," says Emmanuel Antonarakis, M.D., Assistant Professor of Oncology at Johns Hopkins and lead author on the study.

Emmanuel Antonarakis, MBBCh
"Patients whose blood samples contained AR-V7 got no benefit from either enzalutamide or abiraterone," says Antonarakis. He adds that AR-V7 could appear in patients' blood samples at the very start of therapy or acquired later, after therapy has begun. He says, "This test could be used before starting enzalutamide or abiraterone therapy, and if the test shows the presence of AR-V7, patients may opt for a different therapy. It could also be used to monitor patients during the course of therapy with enzalutamide or abiraterone for AR-V7, providing an indication these drugs may not work for much longer."

Take-home: If large-scale studies validate the findings, the investigators say men with detectable blood levels of AR-V7 should avoid these two drugs and instead take other medicines (such as chemotherapy, perhaps) to treat their prostate cancer.

To read the entire article follow this link to the New England Journal of Medicine (NEJM).

Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J.  AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer.  N Engl J Med. 2014 Sep 3. DOI: 10.1056/NEJMoa1315815

The study was funded by the Prostate Cancer Foundation, the Department of Defense, and the National Institutes of Health's National Cancer Institute (CA058236, CA006973).

Source of Quotations: "Blood test for 'nicked' protein predicts prostate cancer treatment response" at http://www.eurekalert.org/pub_releases/2014-09/jhm-btf_1090214.php

1 comment:

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