Prostate cancer is a disease that is driven by hormones called androgens. These hormones act via proteins called androgen receptors (ARs) to boost the growth of prostate cancer cells, much like keys act via locks to open doors. Therapies for prostate cancer have two general modes of attack: Either to remove the keys (androgens) or block the locks (ARs), in effect slamming the doors to growth. In recent years, "third-generation" therapies for prostate cancer have been developed that are highly effective at removing androgens (e.g., abiraterone) or blocking ARs (e.g., MDV3100), creating a "grand slam" on inhibition of androgen action. These therapies have been recently shown to significantly prolong the survival of men with advanced prostate cancer who have failed all other forms of therapy and would otherwise die of the disease. While these agents hold great promise for improving the survival of a broader group of men with prostate cancer, scientists and clinicians have observed that resistance to these new agents occurs sometimes very rapidly, and the disease that ensues is particularly aggressive. Importantly, the future direction for new therapeutics must lie in developing agents that involve strategies founded on emerging knowledge about how prostate cancer cells evade current tactics to destroy them.

The investigators of this proposed study have been instrumental in discovering how prostate cancer cells become resistant to third-generation therapies. One thing is patently clear: Despite drugs that effectively remove the keys and block the locks, the AR remains active in recurrent prostate cancer. Several means of sustaining the activity of ARs in this restrictive environment have been identified but generally fall into two categories: Cells find new ways to make androgens (i.e., new keys) or the ARs become altered in a way that they no longer require activation by androgens (i.e., automatic opening doors). Investigators on this proposal have discovered a novel way that prostate cancers achieve the latter: Recurrent tumors generate cut-up, shorter ARs that have lost parts that interact with androgen, resulting in the unique capacity to constantly stimulate the growth without requiring androgen. Indeed, these scientists have found that because abiraterone or MDV3100 are better at inhibiting androgen action, the new, shorter androgen-independent ARs are more likely to appear. Additionally, the investigators have produced compelling evidence showing that two of the shorter, androgen-independent ARs most frequently found in prostate cancer have the ability to partner with the longer, hormone-dependent form of the AR, helping it to act in the absence of hormone. Finally, and most importantly, the presence of the shorter ARs, alone or together with the more normal, longer ARs, is associated with a new capacity to drive prostate cancer growth that is characteristic of disease resistant to currently available therapies. These findings provide two new opportunities that will be pursued in this proposal: (1) Test whether a new generation of drugs that effectively target both androgen-dependent (i.e., long) and androgen-independent (i.e., short) ARs will be highly effective in treating prostate cancer, particularly for those men with fatal disease, and (2) Determine whether the presence of androgen- independent (short) ARs or markers of their activity can be used to select patients who will most likely benefit from these treatments.

The investigators in this grant proposal have designed two new-generation prostate cancer therapies that target both the long and short (hormone-dependent and hormone-independent) forms of ARs. They have already tested these therapies in preclinical models and found them to be very effective, nontoxic, and easily administered by mouth. The two novel agents will be introduced into clinical trials as part of this project, which aims to be visionary about future therapy for prostate cancer by providing new options for men that progress after treatment with abiraterone or MDV3100. Currently, there are no further options for these men other than highly toxic chemotherapies that may prolong life but severely dampen the quality of it. Ultimately, it is envisioned that men with lethal prostate cancer that have evidence of the short ARs or markers of their activity in metastatic biopsies may benefit from therapy with these new agents. The investigators will also develop clinical tools to facilitate the success of these new-generation drugs, which will enter the clinical arena during the course of this study.

In summary, we have convened a diverse, talented international team of scientists and clinicians to transform prostate cancer therapy by utilizing their leading-edge knowledge about resistance to current anti-androgen drugs to develop novel drugs that inhibit both the long (androgen-dependent) and short (androgen-independent) forms of AR to circumvent evolution of treatment resistance. We expect that within 5 years, our efforts will have given the survival rate from metastatic prostate cancer a big push forward.