UCSF Researcher Puts Focus on AR Resistance Mechanisms

Terence Friedlander, MD

Terence Friedlander, MD, specializes in understanding the basic biology of genitourinary cancer, in particular cancer of the bladder and prostate, in developing new treatments and studying new ways to overcome treatment resistance. An academic medical oncologist at the University of California, San Francisco (UCSF), Friedlander is particularly interested in the specific genetic changes in prostate cancer cells that occur during the development and progression of castration resistance and in the use of novel therapies to overcome this resistance.

Please briefly describe your research interests as they relate to androgen receptor signaling in cancer.

It has been shown that treatment with therapies that lower testosterone to castrate levels for men with metastatic prostate cancer induce genetic changes in the androgen receptor (AR) gene (including amplification of the gene, mutation of the gene, and alternative splicing) or in the cancer cell itself (ie, production of testosterone and androgens by tumor cells themselves in the local tumor microenvironment), and that these changes help keep the AR signaling and allow the cancer cells to survive and grow in a low testosterone (castrate) environment.

A number of new therapies have been developed which more potently inhibit AR and AR signaling, and I am interested specifically in understanding which changes occur and in how to develop strategies to overcome this resistance.

How is AR signaling implicated in the development of cancer?

The AR is present in normal, healthy, prostate cells and binds to testosterone and other androgens that circulate in the body. When bound to testosterone, the AR moves to the nucleus of the cell where it “turns on” genes that promote cell growth and survival. Over time, genetic changes occur in these “healthy” prostate cells that allow them to grow and divide uncontrollably. If testosterone is present (as it is for most men), the AR acts as an “on” switch within these cells, continually telling them to grow and survive. This is the reason that castrating therapy (ie, Lupron or orchiectomy) works so well initially—by lowering testosterone levels we can decrease or even stop the signals that come from the AR and without these signals the cancer cells are unable to grow effectively.

The challenge, as discussed above, is that over time cancer cells develop genetic changes that allow the AR to “wake up” and start signaling again, despite the low-testosterone environment. This inevitably leads to growth and spread of the disease, which can be lethal.

In your opinion, what are the most promising strategies for targeting the AR for cancer therapy?

With the understanding that the growth of castrationresistant prostate cancer (CRPC) is in most cases fueled by resurgent AR signaling, a number of new therapies have been developed. The two most promising approaches involve either blocking the production of androgens (including androstenedione, DHEA, DHEA-S, and others that are not blocked by Lupron or by orchiectomy), or by inhibiting the function of the AR itself.

Abiraterone acetate blocks androgen synthesis and has been shown to prolong survival in men with metastatic CRPC. Enzalutamide is a more potent direct inhibitor of the AR that essentially binds to it tightly and prevents it from interacting with androgens or with DNA in the nucleus.

Enzalutamide has also been shown to prolong survival in CRPC. ARN-509 is an agent that is currently in clinical trials and works in a similar way to enzalutamide. In addition, there are a number of others in clinical trials. TOK-001 (galeterone) blocks both androgen synthesis and the AR itself and is in early-phase studies.

Currently, there is a phase III study exploring the benefit of treating patients with CRPC with abiraterone and enzalutamide given at the same time, to see if more potently blocking AR signaling can lead to more profound and longer-lasting responses. Similarly, there are a number of studies exploring the combination of AR-targeted therapy with other novel treatments, such as immunotherapy (sipuleucel-T), radiopharmaceutical therapy (radium-223), or chemotherapy.

A number of studies are also exploring the benefit of more potently blocking AR signaling earlier in the disease course; for example, at the time of initial surgery or initial radiation therapy, or at the time that metastatic disease is first diagnosed. Lastly, there are a number of different agents that seek to slow or stop AR signaling indirectly by blocking other proteins in the cancer cell that help chaperone or facilitate AR function; the heat-shock proteins (HSPs) in particular protect the AR in the cytoplasm of cancer cells, and HSP inhibitors are under evaluation in a number of studies to see whether this approach can slow or stop AR signaling.

What are the most significant hurdles in the development of effective AR-targeted therapies?

Developing new therapies that can delay or stop these changes from occurring, or therapies that can block these altered ARs from signaling, will be important. The combination of abiraterone and enzalutamide mentioned above may delay the development of these resistance mechanisms, but we will need to await the results of the study before recommending this approach routinely.

What is the potential for AR-targeted therapies in other cancers, such as breast cancer?

AR-targeting therapies may have value in other malignancies; however, it is not clear that other cancers are as exquisitely sensitive to androgens as prostate cancer is. It has been kno wn for a long time that a large percentage of breast cancers express the estrogen or progesterone receptors, that signaling through these receptors promotes the growth of breast cancer, and that therapies that lower these hormones or directly block the receptor have clear benefit.

The AR is expressed in some breast cancers; however, it is not clear that AR plays as important a role in these breast cancers as it does in prostate cancer, nor is it clear that blocking AR will have the same effect. Enzalutamide is under investigation in breast cancer that expresses the androgen receptor, and there are studies that are exploring the benefit of abiraterone acetate in breast cancer as well. It remains to be seen how efficacious targeting the AR in breast cancer is, so we will await the results of these studies.

There is some suggestion that the AR may have a role in hepatocellular cancers, but more work remains to be done to see if targeting the AR in this disease will have benefit. I am not aware of AR-targeting therapy in other cancers but it may make sense to evaluate AR inhibition in other hormonally driven cancers, such as very rare cancers of the adrenal gland, and certain very rare, hormonally driven ovarian or testicular tumors.