Exploiting KRAS addiction for lung cancer therapy

利用 KRAS 成瘾进行肺癌治疗

基本信息

批准号：
10474614
负责人：
DAVID A CHERESH
金额：
$ 40.72万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474614
关键词：
3-Dimensional Alveolar Cell Anchorage-Independent Growth Biological Biological Markers Biopsy Cell Adhesion Cell Survival Cells Cellular biology Collection Critical Pathways Data Dependence Development Drug resistance Equilibrium Extracellular Matrix Fostering Galectin 3 Gene Expression Genetically Engineered Mouse Goals Growth Human In Vitro Individual Integrin alphaVbeta3 Integrins K-ras mouse model KRAS oncogenesis KRAS2 gene Learning Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Modeling Molecular Mus Mutation Nature Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nutrient Outcome Oxidation-Reduction Pathway interactions Phenotype Physicians Play Regulation Reporting Role Scientist Signal Pathway Signal Transduction Surface Surgeon Therapeutic Work addiction adhesion receptor aggressive therapy cancer cell cancer initiation cancer therapy design experimental study in vivo inhibitor insight mouse model mutant neoplastic cell notch protein novel novel strategies novel therapeutics patient derived xenograft model programs receptor function recruit self-renewal stem stress tolerance targeted agent targeted treatment therapy resistant tool tumor tumor addiction tumor growth tumor initiation tumor progression tumorigenesis uptake

项目摘要

Project Summary/Abstract Exploiting KRAS addiction for lung cancer therapy There is a great unmet need to develop new approaches for KRAS mutant lung cancers. While 25-30% of lung adenocarcinomas arise by virtue of activating KRAS mutations, individual tumors may develop KRAS indifference over the course of cancer progression. It is well-appreciated that cancer cells continue to develop adaptations to support the uncontrolled growth and survival required for tumor progression and metastasis. New data shows that the expression of integrin αvβ3 on KRAS mutant cancer cells predicts which tumors remain dependent on KRAS for tumor growth as well as anchorage-independent growth, a hallmark of cancer that is required for invasion and metastatic spread. While a variety of membrane receptors function by clustering in adherent cells, integrin αvβ3 is unique in its ability to cluster and drive signaling pathways in the absence of extracellular matrix anchoring. The Preliminary Results establish that integrin αvβ3 clustering in non-adherent cells gives rise to KRAS addiction by enabling multiple functions of KRAS that drive stress tolerance, including formation of macropinosomes that facilitate nutrient uptake and promotion of a gene expression program that favors redox balance. The overall goals of this proposal are to define how αvβ3-mediated KRAS clustering promotes survival advantages that drive KRAS addiction and contribute to lung cancer initiation, progression, and metastasis in vivo. Understanding the molecular mechanisms critical for this pathway will foster the design of new therapies to exploit the unique vulnerabilities of KRAS mutant cancers. The Specific Aims of this Multi-PI R01 are designed to understand the cell and molecular biological role for αvβ3 as a regulator of KRAS addiction (Aim 1 – led by Dr. Cheresh) and to learn how this relates to cancer initiation and progression using genetically-engineered mouse models of lung cancer driven by oncogenic Kras (Aim 2 – led by Dr. Onaitis). These findings will enable the logical design of new strategies to target KRAS- addicted cells for cancer therapy (Aim 3 – a collaborative effort). Aim 1: Establish the molecular basis for αvβ3 regulation of KRAS functions in vitro Aim 2: Define the impact of αvβ3 on Kras-driven NSCLC in vivo Aim 3: Exploit KRAS addiction to enhance cancer therapy

项目摘要/摘要利用KRAS成瘾进行肺癌治疗为KRAS突变肺癌开发新方法有很大的未满足。而25-30％肺腺癌是由于激活KRAS突变而产生的，单个肿瘤可能会出现KRAS 对癌症进展过程的冷漠。癌细胞继续发展很充分地欣赏适应以支持肿瘤进展和转移所需的不受控制的生长和存活率。新数据表明，整联蛋白αVβ3在KRAS突变癌细胞上的表达预测了哪些肿瘤保持依赖KRAS的肿瘤生长以及与锚固无关的生长，这是癌症的标志这是入侵和转移扩散所必需的。虽然各种膜受体通过聚类在粘附细胞中的功能，但整联蛋白αVβ3在其中是独一无二的在没有细胞外基质锚固的情况下，能够群集和驱动信号通路。初步结果表明，非粘附细胞中的整联蛋白αVβ3聚类通过启用而导致KRAS成瘾 KRA的多个功能驱动胁迫耐受性，包括形成促进大的大型体体营养摄取和促进有利于氧化还原平衡的基因表达程序。总体目标该建议是定义αVβ3介导的KRAS聚类如何促进驱动KRAS的生存优势成瘾并有助于体内肺癌的启动，进展和转移。了解该途径至关重要的分子机制将促进新疗法的设计以利用独特 KRAS突变癌的脆弱性。该多PI R01的具体目的旨在了解细胞和分子生物学作用 αVβ3是KRAS成瘾的调节剂（AIM 1 - 由Cheresh博士领导），并了解这与癌症有何关系使用致癌KRAS的肺癌驱动的一般设计的小鼠模型的起始和进展（AIM 2 - 由Anaitis博士领导）。这些发现将使新策略的逻辑设计能够针对Kras- 用于癌症治疗的加性细胞（AIM 3 - 协作努力）。 AIM 1：建立KRAS在体外功能的αVβ3调节的分子基础 AIM 2：定义αVβ3对KRAS驱动的NSCLC在体内的影响目标3：利用KRAS成瘾来增强癌症治疗