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

摘要： 全世界每年新发现的肾细胞癌病例超过40万例。其中的四分之一 确诊时，患者已经是晚期；用目前的治疗方法，他们预计5年的存活率 利率只有12%。为了帮助减少这种生命损失，巴克斯治疗公司创造了一系列新的分子 在肾癌临床前动物模型中导致肿瘤消退。这些潜在的疗法提供了长期的- 长期存活，而不仅仅是延缓肿瘤生长。这些化合物也显示出对其他化合物的效力 由MYC癌基因驱动的癌症，包括肝细胞癌和B细胞淋巴瘤。 拟议的第一阶段SBIR项目的目标是表征7种生物化学特性和细胞毒性 候选分子，这将确定开发成有效抗肾癌药物的主要候选药物。 初步研究将确定分子的溶解度，以及它们目标酶的专一性。其他内容 工作将评估它们对肾癌和正常细胞系的相对毒性。根据这些结果，候选人 将在肾癌的小鼠模型中进行测试，使用患者来源的异种移植物 表达高水平或低水平的MYC。 在成功完成这些目标后，我们将寻求第二阶段SBIR拨款，以进行以下研究 将使研究新药开发成为可能。通过合作或授权，我们计划将 先导化合物作为一种全新的治疗晚期肾癌的药物。未来的工作将评估 该分子或相关类似物用于治疗其他MYC驱动的癌症。

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.