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

项目总结/摘要 5年生存率为10- 15%，转移性肾细胞癌（RCC）在很大程度上是不可治愈的。酪氨酸激酶 抑制剂（TKI）是用于RCC治疗的最大和最广泛使用的药物类别（6种FDA批准的药物）， 但耐药性通常会产生。第一批TKI在近20年前获得了FDA的批准，但如何 抵抗力的产生仍然是一个谜。开发RCC TKI靶向血管内皮生长因子 受体2（VEGFR 2），其在血管生成和RCC生物学中起关键作用。然而，VEGFR 2的作用 在介导抗肿瘤反应方面仍有待证实，大多数RCC TKI靶向多种其他靶点， 激酶。了解耐药机制有助于剖析肿瘤药物 精确的工作。因此，RCC TKI如何发挥作用仍然是个谜，这代表了一个重要的， 长期存在的重大知识差距。此外，了解激酶抑制剂如何发挥其抗- 肿瘤效应和耐药性如何发展往往为药物开发提供新的途径。的确，相关 其他激酶抑制剂的靶点已经在多种肿瘤类型中得到鉴定和验证， 使第二代和第三代抑制剂得以发展。该提案旨在了解如何 卡博替尼可以说是FDA批准的用于RCC的最有效的TKI，其功能是抑制肿瘤生长，以及如何抑制肿瘤生长。 产生了抵抗。卡博替尼抑制在肿瘤细胞中起作用的肿瘤驱动激酶家族（例如， AXL、MET、RET和KIT）和肿瘤微环境（如VEGFR 2）。一种可能的解释是 为什么RCC TKI如何发挥作用仍有待确定， 微环境（TME）在其抗肿瘤作用中起着关键作用。这份提案不仅将评估如何 卡博替尼影响肿瘤细胞，但也影响TME。然而，剖析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 开创性的小鼠模型，首次剖析了TME在介导卡博替尼抗肿瘤中的作用 反应如果成功，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 卡博替尼如何发挥作用以及耐药性是如何获得的，我们将准备制定策略来克服 阻力本文提出的创新范例具有广泛的应用，可以剖析 微环境在介导任何癌症药物的作用，以及随后的发现可能铺平道路， 下一代抑制剂，并使合理的组合。

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.