Dissecting the mechanism of cabozantinib anti-tumor effect in renal cancer
解析卡博替尼抗肾癌作用机制
基本信息
- 批准号:10443836
- 负责人:
- 金额:$ 22.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAntineoplastic AgentsAntitumor ResponseAutomobile DrivingBiologyCRISPR/Cas technologyCancer ModelDevelopmentDrug resistanceEngineeringFDA approvedFamilyGenerationsGenetic EngineeringGrowthImplantKDR geneKnowledgeMediatingMetastatic Renal Cell CancerMethodsMusMutationNOD/SCID mouseOncologyPatientsPharmaceutical PreparationsPhosphotransferasesPlayRenal Cell CarcinomaRenal carcinomaResistanceResistance developmentRoleSamplingSilicon DioxideSurvival RateTimeTransplantationTyrosine Kinase InhibitorVEGFA geneWorkXenograft procedureangiogenesisantitumor effectdrug developmentembryonic stem cellexperimental studygenetic manipulationinhibitorinnovationkinase inhibitormouse modelneoplastic cellnext generationresistance mechanismtherapy resistanttumortumor growthtumor microenvironment
项目摘要
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.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
James Brugarolas其他文献
James Brugarolas的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('James Brugarolas', 18)}}的其他基金
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:
10289979 - 财政年份:2021
- 资助金额:
$ 22.54万 - 项目类别:
The University of Texas Southwestern Medical Center SPORE in Kidney Cancer
德克萨斯大学西南医学中心 SPORE 在肾癌中的应用
- 批准号:
9071063 - 财政年份:2016
- 资助金额:
$ 22.54万 - 项目类别:
The University of Texas Southwestern Medical Center SPORE in Kidney Cancer
德克萨斯大学西南医学中心 SPORE 在肾癌中的应用
- 批准号:
9752982 - 财政年份:2016
- 资助金额:
$ 22.54万 - 项目类别:
University of Texas Southwestern Medical Center SPORE in Kidney Cancer
德克萨斯大学西南医学中心 SPORE 在肾癌中的应用
- 批准号:
10706530 - 财政年份:2016
- 资助金额:
$ 22.54万 - 项目类别:
Project 1: Targeting HIF2 in Renal Cell Carcinoma
项目 1:针对肾细胞癌中的 HIF2
- 批准号:
10708828 - 财政年份:2016
- 资助金额:
$ 22.54万 - 项目类别:
Evaluation of the BAP1 tumor suppressor gene in renal cell carcinoma
BAP1抑癌基因在肾细胞癌中的评价
- 批准号:
9008030 - 财政年份:2013
- 资助金额:
$ 22.54万 - 项目类别:
相似海外基金
Delays in Acquisition of Oral Antineoplastic Agents
口服抗肿瘤药物的获取延迟
- 批准号:
9975367 - 财政年份:2020
- 资助金额:
$ 22.54万 - 项目类别:
Eliminate the difficulty of venous puncture in patients receiving antineoplastic agents - Development of a new strategy for the prevention of induration-
消除接受抗肿瘤药物的患者静脉穿刺的困难 - 制定预防硬结的新策略 -
- 批准号:
16K11932 - 财政年份:2016
- 资助金额:
$ 22.54万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular mechanisms of the antineoplastic agents inhibiting DNA replication and their applications to cancer patient treatmen
抗肿瘤药物抑制DNA复制的分子机制及其在癌症患者治疗中的应用
- 批准号:
19591274 - 财政年份:2007
- 资助金额:
$ 22.54万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
PNET EXPERIMENTAL THERAPEUTICS--ANTINEOPLASTIC AGENTS AND TREATMENT DELIVERY
PNET 实验治疗——抗肿瘤药物和治疗实施
- 批准号:
6346309 - 财政年份:2000
- 资助金额:
$ 22.54万 - 项目类别:
TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS
酪氨酸激酶抑制剂作为抗肿瘤剂
- 批准号:
2885074 - 财政年份:1999
- 资助金额:
$ 22.54万 - 项目类别:
TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS
酪氨酸激酶抑制剂作为抗肿瘤剂
- 批准号:
6174221 - 财政年份:1999
- 资助金额:
$ 22.54万 - 项目类别: