Anti-Androgens Treatment Enhances Cytotoxicity of Oxidative-Phosphorylation Inhibitors against Castration-Resistant Prostate Cancer
Abstract
Rationale, Objective, and Aims of the Application: Advanced castrate resistant metastatic prostate cancer is the second leading cause of cancer-deaths in U.S. men. Most patients with progressing prostate cancer (PCa) undergo androgen deprivation therapy (ADT) followed by or in combination with anti-androgen therapies. Most of them fail these therapies and progress to castrate-resistant PCa (CRPC), followed by metastatic PCa (mCRPC) with poor prognosis. Developing new therapies against CRPC that has become resistant to standard-of-care antiandrogen therapy is a rarity. Despite intense research during the last decade, the mechanism of developing resistance to anti-androgens remains mostly unknown. We have generated strong preliminary data that suggest that a specific metabolic adaptation of PCa cells changes the metabolism, organization, and distribution of a ubiquitous cellular organelle mitochondrion that is one of the main sources of energy for cancer cell migration and metastasis. Currently, there exist few validated methods of monitoring metabolic changes in tumor tissues in live animals or patients. Here, we propose to cross-validate three overlapping assays that can monitor mitochondrial metabolism in cultured cells, patient-derived tumor xenografts (PDX) in mice, and circulating human tumor cells (CTCs) in PDX carrying mice, as well as in patient blood samples. We believe PCa cells going through such metabolic adaptation will be vulnerable to new mitochondrial metabolism targeted agents that are undergoing clinical development for treatment of several solid tumors, including PCa. Study of the state of these metabolic changes in patient CTCs will allow us to identify patients who will be most benefited from the treatment with these new agents. Based on these data, we hypothesize that the metabolic switch in anti-androgen-treated PCa cells from glucose metabolism to mitochondrial metabolism contributes to developing resistance to AR-targeted therapies and results in mitochondrial reorganization. The cells, thus adapted, are dependent on ox-phos for their energy needs and, therefore, will be vulnerable to mitochondria targeted drugs. We will use rare resources such as several patient derived PDXs developed from metastatic tissues from prostate cancer patients before and after developing resistance to anti-androgen therapy available in our Department. Here, we propose to validate the metabolic adaptation as one of the mechanisms of PCa progression in cultured cells and in carefully selected PDX models in vivo. We will then apply this method to follow patients undergoing antiandrogen therapy to correlate such metabolic changes detected in CTCs obtained from patient blood samples with their disease progression. This will help identify the patients who are developing resistance to standard-of-care anti-androgen therapy and will be most benefited by the treatment with new agents targeting cellular metabolism. Our Specific Aims are: 1(a). To confirm the metabolic switch from glycolysis to ox-phos in androgen-dependent and castrate-resistant human PCa cell lines treated with enzalutamide (ENZA) and test the effects of mitochondrial metabolism inhibitor IACS against cells at this metabolic state. 1(b) To define the role of the metabolic switch in mitochondrial reorganization and ENZA resistance. 2. To observe such metabolic adaptation in PCa PDX tissues and CTCs in intact and castrated animals and test the growth inhibitory effect of IACS in PDXs with or without ENZA pretreatment. 3. To monitor the tumor metabolic adaptation status by analyzing the mitochondrial metabolism CTCs from patient blood samples before, during, and after development of resistance to ENZA using fluorescence microscopy. Ultimate Applicability of the Research: This proposal directly addresses an overarching challenge in PCa: Define the biology of lethal prostate cancer to reduce death. Developing new therapies activ
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010306
Entities
People
- George Wilding
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army