Development of synthetic sphingolipids for prostate cancer therapy

点击翻译按钮获取中文摘要

PROJECT SUMMARY The objective of this project is to develop the synthetic sphingolipid SGE-893 (893) into an FDA-approved cancer therapy, with the ultimate goal of reducing mortality and morbidity rates in end-stage, drug-resistant prostate cancer. 893 shows promising pharmacological characteristics and potent anti-cancer activity in pre-clinical models while sparing normal tissues. 893 and related molecules have a novel mechanism of action, simultaneously engaging two validated oncology targets. This dual-target approach is deadly to cancer cells and predicted to reduce the risk of resistance. Despite its pleiotropic actions, 893 is well-tolerated by normal proliferating cells. Thus, 893 shows potential as a single-agent therapy that could produce a durable response even in hard-to-treat cancers like late-stage prostate, for which systemic chemotherapy remains the standard- of-care (SOC) and high recurrence and mortality rates are driven by resistance. As 893’s mechanism of action further suggests that it could sensitize drug-resistant tumors to FDA-approved agents, 893 may have additional clinical applications as a component of combination therapy. With key de-risking studies completed, we are proposing a Direct-to-Phase II approach. The objectives of Aim 1 are to extend the Target Product Profile by evaluating efficacy in combination with FDA-approved agents and to validate pharmacodynamics markers that can be used to measure target engagement in a phase 1 trial. Aim 2 proposes toxicology studies required for an IND application. The expected results would become part of a strong portfolio demonstrating acceptable toxicity to share with the FDA. Were it to be approved for patient use, this innovative molecule would become a first-in- class compound, offering hope and reducing mortality in PC patients whose tumors fail to respond to or become resistant to SOC.