Therapeutic Targeting of a Master Regulator of Androgen Receptor-Indifferent Prostate Cancer
Abstract
Prostate cancer is a hormone-dependent malignancy driven by the androgen receptor (AR), a protein that, in normal physiology, controls masculinization and virilization in men. In cancer, the AR takes on a cancer-promoting role and acts to stimulate tumor growth and metastasis. Inhibition of AR activity by pharmacologic agents has been a leading strategy to treat prostate cancer for decades. “Next generation” hormonal therapies are still largely directed toward inhibiting AR activity. Even with the latest drugs, medical therapy often fails and “castration-resistant” disease (CRPC) emerges. Once prostate cancer reaches this stage, there are no effective therapeutic options, and death occurs in the majority of cases. The well-known clinical observation that AR-targeted therapy is ultimately ineffective suggests that molecular mechanisms are activated in castration-resistant tumor cells in which the central role of the AR in driving the cancer is either reduced or absent. Recent studies of drug-resistant prostate cancer have revealed that aggressive tumors can be “AR-indifferent,” even though the AR is still present in these tumors. There is no known treatment for this type of prostate cancer, and progression to end-stage disease is largely inevitable. We reported this year in Nature Medicine our discovery that a gene regulatory protein called ONECUT2 (abbreviated OC2 in the proposal) plays a critical role in one-third or more of castration-resistant prostate cancers. Importantly, we have also discovered that this protein can be inhibited by a novel drug-like chemical compound, CSRM617, which we isolated from a large chemical library screen. We have shown that this first-infield chemical agent inhibits growth of established metastases formed by very aggressive human castration-resistant prostate cells in mice, with no detectable toxicity. We have also developed evidence, using both molecular and quantitative pathology approaches, that tumors where OC2 is active can be identified using clinically relevant technologies. If these methods were refined for clinical use, patients who may respond to an OC2 inhibitor could be identified from a tissue or blood sample. This proposal describes the next step in our attempt to translate these exciting findings to patients. Here we will use an established genetic model of human prostate cancer to test the hypothesis that cells where OC2 is active are cells of origin for lethal prostate cancer. We will use this model, as well as an extensive and unique resource of human prostate cancer tissues, to identify other “master regulator” proteins that OC2 cooperates with. This information can be used to extend our insights into how OC2 works, and how it might be targeted therapeutically. This study will also provide a store of provisional markers that will allow us to identify patients most likely to respond to anti-OC2 therapy. The experimental approach we describe here will open a translational pathway toward clinical application of an entirely new therapeutic strategy that could be used to benefit a large percentage of patients with drug-resistant prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910523
Entities
People
- Michael R Freeman
Organizations
- Cedars-Sinai Medical Center
- United States Army