Overcoming Treatment Resistance in Advanced Prostate Cancer

white haired man looking thoughtful

Hormone therapy has long been the center of care for prostate cancer and helps many men diagnosed with the disease live longer. Such treatments reduce or block the production of androgens, the male sex hormones that help prostate cells grow and function, but which also fuel cancer cell growth. Proteins in prostate cells, called androgen receptors (AR) drive this process.

"AR proteins are the master regulators in prostate cells," says Scott Dehm, PhD, an associate professor at the Masonic Cancer Center at the University of Minnesota. "The prostate gland doesn't even form in men if the AR isn't functional."

Scott Dehm, PhD

Most of the time, the AR protein is "turned off." When androgen hormones, like testosterone, move through the bloodstream, they attach to these AR proteins, switching them "on." This triggers a complex process of genetic signaling that tells prostate cells to reproduce.

If and when prostate cancer develops, the cancer cells at first retain their dependence on these AR proteins. In other words, they need androgens to grow. But over time, the cancer cells adapt, and can grow and spread even when men have low levels of testosterone and other androgens.

"That's why therapies to remove testosterone are initially very effective but with time, they fail," Dehm says. "Once they do fail, that's the type of prostate cancer that kills patients. That is what is responsible for prostate cancer being the second leading cause of male cancer death."

The type of prostate cancer Dehm is referring to is called castration-resistant, androgen-independent, or androgen-refractory cancer. There is currently no effective treatment. He hopes to change that. In the last three years, armed with a grant from the American Cancer Society, he has made considerable strides in understanding the genetics of prostate cancer and how it thrives in an androgen-free environment.

Altering the Cancer Blueprint

Understanding how and why prostate cancer changes from a disease that responds to androgen-targeting therapies to one that resists such treatment is a focus of Dehm's research. He has made a major discovery during the time he had his Society grant. He published his findings in several scientific journals, including the October 22, 2013 issue of Proceedings of the National Academy of Sciences of the United States of America.

Dehm’s finding: There are gene-level changes within prostate cancer cells that alter the blueprint for how the AR protein is made. This results in different forms of the receptor with two important new characteristics.

One, the part of the protein targeted by anti-androgen drugs during prostate cancer treatment is missing.

Two, these new forms of the androgen receptor are always active. "They don't need the testosterone signal to turn them on anymore. The activated receptors can constantly provide the cancer cell with the signal that would otherwise be provided by testosterone," says Dehm.

A next step is to determine if these novel versions of AR represent an important contributor to resistance in most patients with prostate cancer, or if they are the key driver of resistance in only a subset of patients. Dehm is now pursuing clinical studies to determine what percentage of men with castration-resistant cancer develop resistance through this newly identified manner. The foundation of knowledge he gained from his Society grant has helped him secure additional funding from other organizations to conduct this new work.

"How Can They Be Targeted?"

The discoveries made by Dehm have highlighted a potential new vulnerability within prostate cancer cells.

"Now that we know that these forms of AR exist within tumors cells and they don't respond to anti-androgens, the questions become how can they be targeted and what do they respond to?" Dehm asks. "If we can find ways to inhibit these new forms that are always on, it may provide a benefit for patients with advanced prostate cancer."

The ultimate goal is that this research leads to the development of new hormone-targeted drugs that work better and longer to keep prostate cancer from spreading. Dehm also believes his findings could be used to guide therapy and prevent anti-androgen medications from being used when the cancer is resistant to it.

"It could be used as a biomarker to make sure the right patient is given the right medicine at the right time in their therapy," he says. Anti-androgen "therapies are not without side effects. It would be undesirable to experience the side effects if it is not going to help rid them of their cancer."

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