Development of synthetic sphingolipids for prostate cancer therapy

项目摘要 该项目的目标是将合成鞘脂SGE-893（893）开发成FDA批准的癌症 最终目标是降低终末期耐药前列腺的死亡率和发病率。 癌893在临床前研究中显示出良好的药理学特性和有效的抗癌活性 模型，同时保留正常组织。893和相关分子具有新的作用机制， 同时使用两个经过验证的肿瘤学靶点。这种双靶点方法对癌细胞是致命的， 预计会降低耐药性的风险。尽管其多效性作用，893是良好的耐受性正常 增殖细胞因此，893显示出作为单药治疗的潜力，可以产生持久的反应 即使是像晚期前列腺癌这样难以治疗的癌症，全身化疗仍然是标准， 耐药性导致了高复发率和高死亡率。AS 893的作用机制 进一步表明，它可以使耐药肿瘤对FDA批准的药物敏感，893可能具有额外的 作为联合治疗的组成部分的临床应用。随着关键的降低风险研究的完成，我们 提出了直接进入第二阶段的方法。目标1的目标是通过以下方式扩展目标产品概况： 评估与FDA批准的药物联合使用的疗效，并验证药效学标志物， 可用于测量1期试验中的目标参与。目标2提出了一项毒理学研究， IND申请。预期结果将成为证明可接受毒性的强大组合的一部分 与FDA分享。如果它被批准用于患者使用，这种创新分子将成为第一个 类化合物，提供了希望，并降低死亡率的PC患者的肿瘤没有反应或成为 抗SOC。

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.