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

项目摘要/摘要 转移性肾细胞癌(RCC)的5年生存率为10%-15%，在很大程度上是无法治愈的。酪氨酸激酶 抑制剂(TKI)是治疗肾癌的最大和最广泛使用的药物类别(6种FDA批准的药物)， 但抗药性是例行公事的。第一批TKIs是在近20年前由FDA批准的，但如何 抵抗力的产生一直是个谜。RCC TKI被开发为靶向血管内皮生长因子 受体2(VEGFR2)，在血管生成和肾细胞癌生物学中发挥重要作用。然而，VEGFR2的一个角色 在介导抗肿瘤反应方面，大多数肾癌TKI靶向多个其他靶点 激活剂。了解耐药机制有助于剖析肿瘤药物如何 准确地说是工作。因此，RCC TKIS如何发挥作用仍然是个谜，这代表着一个重要的、 长期而关键的知识鸿沟。此外，了解激酶抑制剂如何发挥其抗 肿瘤效应和耐药性的产生往往为药物开发提供了新的途径。的确，与此相关 其他激酶抑制剂的靶点已经在多种肿瘤类型中被识别和验证，这已经 使第二代和第三代抑制剂的开发成为可能。这项提议试图理解如何 Cabozantinib，可以说是FDA批准的治疗肾癌的最有效的TKI，其抑制肿瘤生长的功能以及如何 抵抗力就会产生。卡波赞替尼抑制一系列在肿瘤细胞中起作用的肿瘤驱动蛋白(如 AXL、MET、RET和KIT)和肿瘤微环境(如VEGFR2)。一种可能的解释是 为什么RCC TKIs如何发挥作用仍有待确定，原因是肿瘤中的激酶受到抑制 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 卡波赞替尼不仅影响肿瘤细胞，而且还影响TME。然而，剖析TME在 抗肿瘤反应是具有挑战性的，需要创新的方法。该提案将利用 首开先河的小鼠模型首次剖析了TME在介导卡波赞替尼抗肿瘤中的作用 回应。如果成功，这些研究将确定库赞替尼是如何发挥其抗肿瘤活性的。通过定义 如何发挥作用以及如何获得耐药性，我们将准备制定策略，以克服 抵抗。本文提出的创新范式广泛应用于剖析 微环境调节任何抗癌药物的作用，以及随后的发现可能为 下一代抑制剂并实现合理的组合。

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.