Tumor Metabolism as the Achilles Heel in Prostate Cancer
Abstract
Prostate cancer progresses to a castration-resistant stage after the failure of androgen ablation therapy. The current regimen for therapy of castration-resistant prostate cancer includes targeted therapeutics such as enzalutamide or abiraterone and chemotherapeutics such as docetaxel or cabazitaxel. Clinical observations of resistance developing within 9-15 months of treatment diminish the efficacy of enzalutamide or abiraterone. Thus, the need of the hour is combinatorial strategies to overcome acquired resistance to such agents. Unlike other solid tumors, prostate cancer is unique metabolically and does not glucose metabolism known as glycolysis until the advanced stages. In advanced prostate cancer, glycolysis produces high levels of the byproduct lactate, a monocarboxylic acid, which, if not exported, will be toxic to cells. Hence, prostate cancer cells upregulate the expression of genes such as monocarboxylate transporters (MCTs) to aid in lactate export. High levels of expression of MCTs have been associated with poor prognosis and biochemical failure in prostate cancer. Our preliminary data show that the expression levels of MCTs are high in prostate cancer cells resistant to several therapeutics compared with therapy-sensitive ones. We tested whether inhibition of MCT activity can suppress cancer cell survival and found that, not only does MCT inhibition suppress proliferation of prostate cancer cells, it also resensitizes resistant cells to treatment with enzalutamide. Based on these data, we hypothesize that MCT inhibition may be a viable strategy to overcome therapy resistance. We propose three specific aims to test this hypothesis. In Aim 1, we will undertake a comprehensive characterization of the effects of MCT inhibitors AR-C155858, AZD3965, or syrosingopine either singly or in combination with enzalutamide using a panel of therapy resistant prostate cancer cell lines. These results will be confirmed using inhibition of MCT expression. In Aim 2, we will assess the ability of MCT inhibitors to suppress the tumor growth of therapy-resistant prostate cancer cells and patient-derived tissues in mice. In Aim 3, we will explore the mechanisms involved in the effects seen with MCT inhibitors. We believe this proposal is one of the first to explore the concept of metabolic targeting to overcome therapy resistance in prostate cancer. Hence, it is highly innovative and may have enormous impact on the future of prostate cancer research. This proposal addresses the FY19 PCRP Overarching Challenges, “develop treatments that improve outcomes for men with lethal prostate cancer” and “define the biology of lethal prostate cancer to reduce death.” If successful, results from this proposal will help patients with prostate cancer that has progressed on enzalutamide. Potential clinical application will be in the enzalutamide-resistant prostate cancer patient population, which is a subset of patients that do not currently have many options. Even though the drugs to be tested will have to go through clinical evaluation, toxicity testing, and clinical trials in prostate cancer patients, they are already in clinical trials for other cancers, and the timeline for potential clinical applicability in prostate cancer may be relatively short.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010794
Entities
People
- Nagalakshmi Nadiminty
Organizations
- United States Army
- University of Toledo Health Science Campus