Inducing Apoptosis in Castration- Resistant Prostate Cancer by Targeting Sphingomyelin Synthase 1 for mono and combination therapy

Idaho State University, Pocatello ID

Investigators

Abstract

Project Summary In aging men ≥ 65 years, prostate cancer (PC) is the most common cancer especially for treatment evading resistant variants. The goal of this project is to develop ceramide mimics based sphingomyelin synthase 1 (SMS1) inhibitors for the treatment of castration-resistant prostate cancer (CRPC) by preventing Ceramide (Cer) metabolism. Upregulation of ceramide-metabolizing enzymes, included with concomitant reduction in cellular ceramide levels, is observed in aggressive cancers, including CRPC. This activity is also associated with increased resistance to apoptosis and with biosynthesis of secondary metabolites that promote cell survival. Strategies that increase ceramide thus hold potential for treatment of refractory cancers. Targeting ceramide metabolism in-conjunction with FDA approved pharmacological interventions has promise in treating CRPC. Ceramide mimic - Jaspine B, a naturally-occurring ceramide mimic, inhibits sphingomyelin synthase (SMS) - a key ceramide-metabolizing enzyme. In a team effort, our laboratory identified jaspine B exhibited dose-dependent cytotoxicity against melanoma and sarcoma cells in culture that was associated with increased caspase-3/7 activity. Jaspine B also displayed marked therapeutic efficacy in our in vivo synovial sarcoma model. These strong preliminary data support a medicinal chemistry program to improve the drug-like properties of molecules. The efficacy of jaspine B in CRPC will be validated in two well characterized prostate cancer cell lines and in a relevant patient-derived xenograph (PDX) mouse model. The goals of the proposed research are to: 1) Evaluate the efficacy of SMS1 inhibition by jaspine B in CRPC. 2) Improve jaspine B- mediated SMS1 inhibition through analog synthesis and/or combination therapy. 3) Delineate the possible mechanisms of resistance of SMS1 inhibition. The completion of the project will identify a Lead molecule based on jaspine B core targeting SMS1 in CRPC, identify a probe to interrogate ceramide flux. The major innovation of this project is the therapeutic development of sphingolipid membrane biochemistry using the ceramide mimic jaspine B core. We aim to show the significance of sphingolipids in combination therapy with FDA approved anticancer agents. This project will have a significant impact on undergraduate and graduate student training at Idaho State University.