Development of synthetic sphingolipids for prostate cancer therapy

开发用于前列腺癌治疗的合成鞘脂

• 批准号: 10157470
• 负责人: Daniel Gil
• 金额: $ 100.88万
• 依托单位: SIEGE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157470
• 关键词: Address; Amino Acids; Androgen Receptor; Antigens; Benchmarking; Bone Marrow; Cancer Patient; Canis familiaris; Cardiovascular system; Cause of Death; Cell Nucleus; Cells; Characteristics; Clinical Research; Clinical Trials Design; Combined Modality Therapy; Cross Presentation; Cytotoxic Chemotherapy; Data; Dendritic Cells; Development; Dose; Dose-Limiting; Drug Kinetics; Drug Sensitization; Drug resistance; Effectiveness; Evaluation; FDA approved; Fasting; Funding; Genes; Genetic Transcription; Genetically Engineered Mouse; Glucose; Goals; Government; Growth; Immunologics; Immunotherapy; Importins; In Vitro; In complete remission; Lead; Lipids; Malignant Neoplasms; Malignant neoplasm of prostate; Maximum Tolerated Dose; Measures; Modeling; Morbidity - disease rate; Mus; Normal Cell; Normal tissue morphology; Nuclear; Nuclear Import; Nutrient; Oncogenic; Oncology; Oral; Organoids; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Population; Pre-Clinical Model; Proliferating; Prostate; Prostate Cancer therapy; Prostate-Specific Antigen; Protein Phosphatase 2A Regulatory Subunit PR53; Protocols documentation; Rattus; Recurrence; Resistance; Risk; Safety; Signal Transduction; Sphingolipids; Stress; Structure-Activity Relationship; Telemetry; Testing; Therapeutic Index; Toxic effect; Toxicology; Tumor Volume; Tumor stage; Work; addiction; anticancer activity; cancer cell; cancer therapy; chemotherapy; clinical application; first-in-human; in vivo; innovation; mortality; neoplastic cell; novel; patient population; pharmacodynamic biomarker; phase I trial; prevent; prostate cancer model; response; risk minimization; standard of care; targeted agent; therapy resistant; trafficking; tumor; tumor growth; tumor metabolism; tumor-immune system interactions

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.

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 临床应用作为联合治疗的一个组成部分。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。