Novel Lineage Plasticity Inhibitors in Prostate Cancer
Abstract
Drug-resistant (castration-resistant) prostate cancer is still largely a lethal disease. Although most patients respond to hormonal therapy, drug resistance is virtually universal. Once treatment failure occurs, progression to end-stage disease is the most common clinical course. In order to improve this depressing clinical picture, new and innovative therapies against aggressive prostate cancer must be developed. Our group has identified a master regulator protein called ONECUT2 (abbreviated OC2) that operates in high-grade and metastatic prostate cancer. Importantly, we have shown that this protein, which regulates gene expression, can be inhibited with a drug-like small molecule that causes regression of established human prostate cancer metastases in mice. We have shown that OC2 activity emerges in prostate tumors that have become drug resistant, but also in aggressive tumors that have not been treated. The reason for activity in hormone-naïve tumors is likely because OC2 activity is induced under conditions of stress, such as tumor regions that are deprived of oxygen (hypoxia). OC2 controls a large network of genes that confer drug resistance. Consequently, inhibiting this protein in patients may suppress disease progression by interfering with multiple molecular mechanisms of resistance to treatment. In unpublished results, we have solved the atomic structure of OC2 bound to DNA. This accomplishment, in concert with the studies proposed here, will allow us to understand how the small molecule inhibitor we have identified actually interferes with OC2 activity. As a result of funding from the NCI SPORE program, we have expanded the initial inhibitor into a family of small molecule OC2 inhibitors to include compounds that are more potent and drug-like. In this Idea Award project, we will use structural biology approaches to characterize these inhibitors at atomic resolution. The information we obtain will teach us precisely – at the level of single atoms – how these OC2 inhibitors work, so we can chemically optimize them and turn them into real drugs. This project will also determine how these inhibitors work in human prostate cancer cells and tissues, and assess their level of specificity in inhibiting only the OC2 target protein, thereby reducing possible side effects. This study is supported by a large amount of published and unpublished data consistent with the hypothesis that OC2 inhibitors can be advanced all the way to patients. Current evidence suggests we will be able to tell, from biomarker tests, which patients are most likely to respond to OC2 inhibitor therapy. Consequently, this study is potentially high-impact and directly addresses the Department of Defense Prostate Cancer Program Overarching Challenge of developing treatments that improve outcomes for men with lethal prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210940
Entities
People
- Michael R Freeman
Organizations
- Cedars-Sinai Medical Center
- United States Army