PSA Rising /DALLAS/ – July 25, 2011 – UT Southwestern Medical Center researchers have narrowed the potential drug targets for advanced prostate cancer by demonstrating that late-stage tumors are driven by a different hormonal pathway than previously was thought.
"We have recently discovered that castration resistant prostate cancer (CRPC) is unexpectedly driven by dihydrotestosterone synthesis from adrenal precursors in a pathway that circumvents testosterone," says Dr. Nima Sharifi, assistant professor of internal medicine and senior author of a study in Proceedings of the National Academy of Sciences.
"The dominant pathway to DHT synthesis from adrenal precursors in CRPC [castration resistant prostate cancer] follows an alternative route that bypasses T and requires steroid 5α-reductase isoenzyme-1 (SRD5A1)," Dr. Sharifi writes.
Prostate cancer cells express higher than normal levels of the enzyme SRD5A1. The 5α-reductase inhibitor . A clinical trial is planned at Dana Farber Cancer Center to test dutasteride plus abiraterone acetate (Zytiga) for metastatic castration resistant prostate cancer.
Upstream of the testosterone blockade
While testosterone is generally known to stimulate the growth of the disease, advanced prostate cancer that is resistant to standard hormonal therapy actually is driven by a pathway that circumvents testosterone, Dr. Sharifi says.
In advanced prostate cancer, testosterone driving the disease is converted into a more potent hormone that speeds up tumor growth. The standard treatment has been to block and deplete testosterone in the tumors, but the cancer cells eventually become resistant to hormone depletion because they make their own androgens, or male hormones.
In the current study, UT Southwestern scientists analyzed prostate cancer cell lines, mouse models and fresh tumor tissue from patients. Their findings suggest that potential drug therapies ought to target an enzyme responsible for initiating hormone production earlier in the process. The specific enzyme found relevant by the current research is as stated steroid 5α-reductase isoenzyme-1 (SRD5A1).
Dr. Sharifi hopes his findings will also help researchers develop accurate biomarkers of response and resistance to hormonal therapies, which eventually will help identify why and how prostate cancer tumors become resistant. He writes in the PNAS article:
Our observation that DHT is synthesized through an alternative pathway involving conversion of AD to 5α-dione by SRD5A1 has broad implications for the development of new therapeutic agents and for determining mechanisms of resistance to hormonal therapies for CRPC. These data suggest that blocking the conversion of AD to T will not significantly inhibit DHT synthesis in CRPC. Furthermore, our findings suggest that T may not be the best marker for monitoring the intratumoral response or resistance to upstream inhibitors of adrenal steroid synthesis, such as abiraterone acetate. Future studies of intratumoral androgens should include previously unappreciated DHT intermediates.
"This now suggests that a potential drug target is one step upstream in the pathway," Sharifi said. "This can be thought of as charting a map of the correct pathway. You have to figure out which way the river flows before you can block the river."
In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.
The study was supported by the Howard Hughes Medical Institute, the Prostate Cancer Foundation, the U.S. Army Medical Research and Materiel Command; the Burroughs Wellcome Fund, and the Charles A. and Elizabeth Ann Sanders Chair in Translational Research.
Dr. Sharifi and and a colleague declare that they have worked as paid consultants to Ortho Biotics, which developed abiraterone acetate, brand name Zytiga. Ortho Biotech, part of Cougar, has been bought out by Janssen Pharmaceutical Companies and Johnson & Johnson. Zytiga was FDA approved after clinical trials showed it extended lives of advanced prostate cancer patients by median 4 months.
Other UT Southwestern researchers participating in the study were lead author Dr. Kai-Hsiung Chang, postdoctoral researcher; Dr. Rui Li, research assistant in internal medicine; Mahboubeh Papri-Zareei, research associate; Dr. Lori Watumull, professor of radiology; Dr. Yan Daniel Zhao, associate professor of clinical sciences and the Simmons Cancer Center; and Dr. Richard J. Auchus, former professor of internal medicine.
Visit Dr. Sharifi's homepage to read his comments on this research and see his previous publications.
This post has been updated on July 30 to include the abstract and to insert a link to upcoming Dana Farber clinical trial of abiraterone acetate (Zytiga) and duasteride (Avodart) plus prednisone for men with metastatic castrate resistant prostate cancer.