In Prostate Cancer, Focus on AR Signaling Sharpens

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)

Vorinostat^a

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.”

Mohler said castration, whether it is achieved medically or surgically, is a catastrophe for the prostate cancer cells in which “little cancer cells are screaming because most of them are dying.” He said that presents an opportunity for treatment with emerging targeted agents, “rather than waiting for the classical CRPC patient who has recurrent cancer all over their body, and they become symptomatic like the old days and you give them docetaxel.”

“What I’m suggesting is, you might want to leapfrog all the way over to the initial androgen deprivation therapy and see if we can cause the catastrophe of castration for these cancer cells to be so severe that you might actually be able to use the ‘cure’ word for some men with advanced prostate cancer,” he said.

At the same time, Mohler said, he would not yet substitute an emerging therapy for a luteinizing hormonereleasing hormone (LHRH) agonist or antagonist in the treatment timeline. “I wouldn’t at this time until you have clinical data that say that that’s possible,” he said. “We may be going that way eventually.”

Reasons for Recurrence Emerge

Despite advances, approximately 30% of patients treated with curative intent, and most patients treated with androgen-deprivation therapy, will experience tumor recurrence, researchers have noted.

Until recently, Mohler said, researchers mistakenly believed that AR genetic mutations broaden ligand specificity, leading to recurrence. Instead, subsequent research has shown that phenomenon is rare and that the AR itself is being activated through metabolic processes.

“Now we know that prostate cancer is not growing independent of androgens when it recurs during androgen deprivation therapy,” said Mohler. “The cancer is still growing, with its growth directed by the androgen receptor, and that androgen receptor has changed itself molecularly so that it is more sensitive, possibly even to castrate levels of testosterone.”

He said the AR responds to castration with changes that cause hypersensitivity to low levels of ligand; laboratory work on cell lines show androgen-independent receptors are 10,000 times more sensitive than androgen-dependent cancer cells. The sensitivity results from changes the AR coactivators undergo in the transcription complex, and ARs also can become phosphorylated.

“The other thing that can happen is that a hypersensitized AR can see more androgen,” he said.

In fact, Mohler and colleagues demonstrated that tissue androgen levels in men whose cancer recurs during androgen-deprivation therapy can be as high as those with benign prostates (Clin Cancer Res. 2004;10:440-448).

Mohler said prostate tissue has a “unique ability” to form its own dihydrotestosterone (DHT), a potent activator of the androgen receptor. The tumor “learns how to make its own testosterone and intracellular active form dihydrotestosterone from weak adrenal androgens by a process called intracrine metabolism,” he said.

Five Pathways Identified

Androgen metabolism is a highly complex process involving a variety of enzymes with as many as 12 isoforms that have been identified with different names over the years, said Mohler. “This is a nightmare of nomenclature and numbers and redundancy,” he said.

Now, a pathways-based understanding of the ways in which prostate cells synthesize DHT is developing. Five pathways have been identified, and cancer cells are able to move to an alternative route if one channel is inhibited (Figure Below). These pathways are:

• The intact pathway, where the testicles are present and DHT is produced via testosterone
• The adrenal pathway, where DHT is synthesized from weak adrenal androgens via testosterone
• The cholesterol pathway, which makes use of cholesterol in the cell membrane or in the bloodstream and turns it into DHT
• A backdoor pathway, in which the prostate cell will generate DHT without having to use testosterone
• A degradatory pathway, in which products of the metabolism of DHT build up to levels that can be turned back into DHT. (Mohler and colleagues recently propounded this theory [Clin Cancer Res. 2011; 17(18); 5844—5849]).

Mohler said the emphasis on these pathways is growing because more is known about the role of 17 hydroxylase/C17,20-lyase (CYP17), an enzyme that is expressed in testicular, adrenal, and prostate tumor tissues and is required for androgen biosynthesis. Inhibiting CYP17A1 “interferes with the metabolism of testosterone from cholesterol adrenal androgens or through the backdoor pathway,” which is the mechanism of action of abiraterone and other agents currently under study, said Mohler.

As research continues, other targets are being identified, he said.

Figure. Pathways to DHT Synthesis

James J. Mohler, MD, detailed the pathways through which DHT can be synthesized during his presentation at the congress.

Source: Adapted from Locke JA, et al. Cancer Res. 2008;68(15):6407-6415.