In Prostate Cancer, Focus on AR Signaling Sharpens

Anita T. Shaffer
Published Online: Tuesday, November 13, 2012
Dr. James L. Mohler

James L. Mohler, MD

The 10th International Congress on Targeted Therapies in Cancer, held August 17-18 in Washington, DC, provided an overview of emerging research into a variety of anticancer targets, including novel hormonal approaches in prostate and breast cancers, and cellsignaling pathways, such as the aurora kinases. Alex A. Adjei, MD, PhD, of Roswell Park Cancer Institute, and John Wright, MD, PhD, of the National Cancer Institute, served as program directors for the meeting, which Physicians’ Education Resource (PER) hosted.

A deeper understanding of androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) has created an opportunity to deliver more effective therapies earlier in the treatment timeline, according to James L. Mohler, MD.

In fact, Mohler believes a strategy of “androgen annihilation” may be the optimal path to curative treatment of men at risk of dying from the disease.

Mohler is associate director and senior vice president for Translational Research at Roswell Park Cancer Institute in Buffalo, New York, where he serves as chair of the Department of Urology and as a professor of Oncology. He also chairs the National Comprehensive Cancer Network’s Prostate Cancer Panel.

During a presentation and interview at the Targeted Therapies congress, Mohler indicated that expanded knowledge about the science of prostate cancer is pointing the way not only to new therapeutics, but also to a new treatment paradigm for CRPC.

In the past 18 months, the FDA has approved two new oral drugs with different mechanisms of action for interfering with androgen activity. In April 2011, the agency approved abiraterone acetate (Zytiga) in combination with prednisone to treat patients with mCRPC who have received prior docetaxel therapy. In August, enzalutamide (Xtandi) gained approval for a similar patient population. Additional agents are in development. (Table).

Table. Agents Targeting Androgen Receptor Signaling

Agent Indication
(approved or under study)
Description Sponsors Status
Abiraterone acetate
(Zytiga)
Given in combination with prednisone to patients with mCRPC who have received prior docetaxel Inhibits CYP17 enzyme activity Janssen Biotech (Johnson & Johnson) FDA approved April 2011
Enzalutamide
(Xtandi)
mCRPC who have previously received docetaxel Inhibits androgen binding to ARs, AR nuclear translocation and interaction with DNA Medivation/ Astellas Pharma FDA approved August 2012
Galeterone
(TOK-001)
Chemotherapy-naïve CRPC Inhibits CYP17 lyase, antagonizes testosterone binding to AR, degrades AR protein Tokai Pharmaceuticals 8-arm ARMOR1 dose-escalation study completed (NCT00959959); phase II study planned
Orteronel
(TAK-700)
mCRPC, chemotherapy-naïve mCRPC Acts as nonsteroidal, selective CYP17 lyase inhibitor Millennium/Takeda Separate phase III studies evaluating orteronel plus prednisone (NCT01193257, NCT01193244)
High-risk patients, defined by Gleason score and PSA; no distant metastases within 90 days   Radiation Therapy Oncology Group/ National Cancer Institute Phase III study evaluating orteronel plus radiation and hormonal therapy (NCT01546987)
Panobinostat
(LBH589)
Recurrent prostate cancer after castration Acts as pan-HDAC inhibitor Novartis/ New York University School of Medicine Phase I/II combination study with bicalutamide (NCT00878436)
Vorinostata Given with androgen-deprivation therapy before radical prostatectomy to patients with localized prostate cancer HDAC inhibitor National Cancer Institute Phase II combination study in patients with stages I-III cancer (NCT00589472)

aVorinostat is approved under the name Zolinza for the treatment of cutaneous T-cell lymphoma.
CYP17 indicates 17 α-hydroxylase/C17,20-lyase; HDAC, histone deacetylase; mCRPC, metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen.

“We’ve learned a lot more about prostate cancer recurrence after the catastrophe of castration,” said Mohler, whose laboratory at Roswell Park has helped lay the scientific groundwork for therapeutic advances. “We have an ample opportunity now to do a better job of inducing response to androgen deprivation therapy. I think we need to move these agents up front and do a better job of killing as many of the prostate cancer cells as possible, and then let our immune system clean up the rest.”

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