Dissecting the mechanism of cabozantinib anti-tumor effect in renal cancer

解析卡博替尼抗肾癌作用机制

• 批准号: 10443836
• 负责人: James Brugarolas
• 金额: $ 22.54万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-02 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443836
• 关键词: Affect; Antineoplastic Agents; Antitumor Response; Automobile Driving; Biology; CRISPR/Cas technology; Cancer Model; Development; Drug resistance; Engineering; FDA approved; Family; Generations; Genetic Engineering; Growth; Implant; KDR gene; Knowledge; Mediating; Metastatic Renal Cell Cancer; Methods; Mus; Mutation; NOD/SCID mouse; Oncology; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; Renal Cell Carcinoma; Renal carcinoma; Resistance; Resistance development; Role; Sampling; Silicon Dioxide; Survival Rate; Time; Transplantation; Tyrosine Kinase Inhibitor; VEGFA gene; Work; Xenograft procedure; angiogenesis; antitumor effect; drug development; embryonic stem cell; experimental study; genetic manipulation; inhibitor; innovation; kinase inhibitor; mouse model; neoplastic cell; next generation; resistance mechanism; therapy resistant; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY/ABSTRACT With 5-year survival rates of 10-15%, metastatic renal cell carcinoma (RCC) is largely incurable. Tyrosine kinase inhibitors (TKIs) are the largest and most widely used class of drugs for RCC treatment (6 FDA-approved drugs), but resistance routinely develops. The first TKIs were approved by the FDA nearly 2 decades ago, but how resistance arises has remained a mystery. RCC TKIs were developed to target vascular endothelial growth factor receptor 2 (VEGFR2), which plays a critical role in angiogenesis and RCC biology. However, a role for VEGFR2 in mediating the anti-tumor response remains to be demonstrated, and most RCC TKIs target multiple other kinases. Understanding resistance mechanisms has been instrumental in dissecting how oncology drugs precisely work. As such, how RCC TKIs function remains enigmatic and this represents a significant, longstanding, and critical knowledge gap. Furthermore, understanding how kinase inhibitors exert their anti- tumor effect and how resistance develops often yields new avenues for drug development. Indeed, relevant targets for other kinase inhibitors have been identified and validated across multiple tumor types, which has enabled the development of second- and third-generation inhibitors. This proposal seeks to understand how cabozantinib, arguably the most potent FDA-approved TKI for RCC, functions to inhibit tumor growth and how resistance develops. Cabozantinib inhibits a family of tumor-driving kinases with roles in tumor cells (such as AXL, MET, RET and KIT) and the tumor microenvironment (such as VEGFR2). One potential explanation for why it remains to be determined how RCC TKIs function is that inhibition of kinases in the tumor microenvironment (TME) plays a critical role in their anti-tumor effects. This proposal will evaluate not only how cabozantinib affects tumor cells, but also how it affects the TME. However, dissecting the role of the TME in the anti-tumor response is challenging and innovative approaches are needed. The proposal will leverage a pioneering mouse model to dissect, for the first time, the role of the TME in mediating cabozantinib anti-tumor response. If successful, these studies will establish how cabozantinib exerts its anti-tumor activity. By defining how cabozantinib functions and how resistance is acquired, we will be poised to develop strategies to overcome resistance. The innovative paradigm presented herein has broad application to dissecting the role of the microenvironment in mediating the action of any cancer drug, and the ensuing discoveries may pave the way for the next generation of inhibitors and enable rational combinations.

项目摘要/摘要 转移性肾细胞癌（RCC）的5年生存率为10-15％，在很大程度上无法治愈。酪氨酸激酶 抑制剂（TKIS）是用于RCC治疗的最大，最广泛使用的药物（6种FDA批准的药物）， 但是阻力通常会发展。第一个TKI被FDA批准了近20年前，但是如何 产生阻力仍然是一个谜。开发RCC TKI以靶向血管内皮生长因子 受体2（VEGFR2），在血管生成和RCC生物学中起关键作用。但是，VEGFR2的角色 在介导抗肿瘤反应时仍有待证明，大多数RCC tkis靶向多个其他 激酶。理解抗药机制一直在解剖肿瘤学药物方面发挥了作用 精确工作。因此，RCC TKIS函数如何保持神秘状态，这代表了一个重要的， 长期存在和批判知识差距。此外，了解激酶抑制剂如何发挥其抗 肿瘤效应以及耐药性发展通常会为药物开发带来新的途径。确实，相关 已经确定并在多种肿瘤类型中鉴定并验证了其他激酶抑制剂的靶标 启用了第二代抑制剂的发展。该提议试图了解如何 Cabozantinib，可以说是RCC最有效的FDA批准的TKI，可抑制肿瘤生长以及如何 阻力发展。卡博替尼抑制在肿瘤细胞中具有作用的肿瘤驱动激酶家族（例如 Axl，Met，RET和试剂盒）和肿瘤微环境（例如VEGFR2）。一个潜在的解释 为什么尚待确定RCC TKIS功能是如何抑制肿瘤中激酶的 微环境（TME）在其抗肿瘤作用中起着至关重要的作用。该建议不仅会评估 Cabozantinib会影响肿瘤细胞，也影响其影响TME。但是，解剖TME在 抗肿瘤反应具有挑战性，需要创新的方法。该提案将利用 开创性小鼠模型首次剖析了TME在介导Cabozantinib抗肿瘤中的作用 回复。如果成功，这些研究将确定卡博替尼如何发挥其抗肿瘤活性。通过定义 Cabozantinib如何功能以及如何获得抵抗力，我们将有望制定克服策略 反抗。本文提出的创新范式在剖析了 微环境介导任何癌症药物的作用，随之而来的发现可能为 下一代的抑制剂和能够理性组合。