Development of lipogenesis inhibitors for tumor regression in renal cell carcinoma and other MYC-driven cancers

开发用于肾细胞癌和其他 MYC 驱动的癌症肿瘤消退的脂肪生成抑制剂

• 批准号: 10253565
• 负责人: Arvin Gouw
• 金额: $ 40.54万
• 依托单位: BACCHUS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253565
• 关键词: Acyltransferase; Animal Model; Animals; Apoptosis; Autopsy; B-Cell Lymphomas; BAY 54-9085; Benign; Biochemical; Biological Assay; CASP3 gene; Cell Line; Cessation of life; Clinical; Clinical Trials; Development; Diagnosis; Dose; Economic Burden; Enzymes; Epithelial Cells; Ethylmaleimide; Excision; Family; Funding; Future; Glucose; Glutamine; Goals; Hepatocyte; Human; In Vitro; Induction of Apoptosis; Intraperitoneal Injections; Investigation; Investigational Drugs; Kidney; Lead; Licensing; Life; Lymphoma cell; MYC Family Protein; MYC gene; Malignant Epithelial Cell; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Membrane; Modeling; Monitor; Mus; Nivolumab; Normal Cell; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phospholipids; Phosphotransferases; Primary carcinoma of the liver cells; Prognosis; Proximal Kidney Tubules; Renal Cell Carcinoma; Research; Small Business Innovation Research Grant; Solubility; Specificity; Stress; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Tumor Volume; Vascular Endothelial Growth Factors; Weight; Work; alpha-glycerophosphoric acid; analog; aqueous; base; cancer cell; cell transformation; cost; cytotoxicity; drug development; in vivo; in vivo Model; in vivo evaluation; inhibitor/antagonist; kidney cell; lead candidate; lipid biosynthesis; lipid metabolism; lipogenesis inhibitor; mouse model; novel; novel therapeutics; patient derived xenograft model; pembrolizumab; pleiotropism; pre-clinical; programmed cell death protein 1; receptor; screening; small molecule inhibitor; trait; tumor; tumor growth

SUMMARY: Over 400,000 new cases of renal cell carcinoma (RCC) are detected annually worldwide. One-fourth of these patients are already in advanced stages when diagnosed; with current therapies, their predicted 5-year survival rate is only 12%. To help curtail this loss of life, Bacchus Therapeutics has created a family of novel molecules that cause regression of tumors in preclinical animal models of RCC. These potential therapeutics provided long- term survival, rather than merely delaying tumor growth. These compounds also showed potency against other cancers driven by the MYC oncogene, including hepatocellular carcinoma and B-cell lymphoma. The goal of the proposed Phase I SBIR project is to characterize the biochemical traits and cytotoxicity of 7 candidate molecules, which will determine a lead candidate for development into an effective drug against RCC. Initial studies will define the solubility of the molecules, as well as specificity for their target enzyme. Additional work will evaluate their relative toxicity to RCC versus normal cell lines. Based on these results, the candidate with the highest specific potency will be tested in mouse models of RCC, using patient-derived xenografts that express either high or low levels of MYC. Following the successful completion of these Aims, we will seek Phase II SBIR funding to undertake studies that will enable Investigational New Drug development. Through partnering or licensing, we plan to commercialize the lead compounds as a completely new therapeutic agent against advanced RCC. Future work will evaluate this molecule or related analogs for treatment of other MYC-driven cancers.

总结： 全世界每年检测到超过40万例新的肾细胞癌（RCC）病例。其中四分之一 患者在诊断时已经处于晚期;使用目前的治疗方法， 率只有12%。为了帮助减少这种生命损失，巴克斯治疗公司创造了一个新的分子家族， 导致RCC临床前动物模型中肿瘤消退。这些潜在的治疗方法提供了长期的- 长期生存，而不仅仅是延缓肿瘤生长。这些化合物也显示出对其他 由MYC癌基因驱动的癌症，包括肝细胞癌和B细胞淋巴瘤。 所提议的第I阶段SBIR项目的目标是表征7种细菌的生化特性和细胞毒性。 候选分子，这将决定一个领先的候选人发展成为一个有效的药物对RCC。 最初的研究将确定分子的溶解度，以及对靶酶的特异性。额外 工作将评估它们对RCC与正常细胞系的相对毒性。根据这些结果，候选人 将在RCC小鼠模型中测试具有最高特异性效力的，使用患者来源的异种移植物， 表达高或低水平的MYC。 在成功完成这些目的后，我们会申请第二期“中小企业改革”拨款，进行研究， 将促进研究性新药开发。通过合作或许可，我们计划将 先导化合物作为治疗晚期肾细胞癌的全新药物。今后的工作将评估 该分子或相关类似物用于治疗其他MYC驱动的癌症。