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

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $191,577

## Abstract

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.

## Key facts

- **NIH application ID:** 10289979
- **Project number:** 1R21CA263264-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** James Brugarolas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $191,577
- **Award type:** 1
- **Project period:** 2021-07-02 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10289979

## Citation

> US National Institutes of Health, RePORTER application 10289979, Dissecting the mechanism of cabozantinib anti-tumor effect in renal cancer (1R21CA263264-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10289979. Licensed CC0.

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