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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

项目概要/摘要利用 KRAS 成瘾进行肺癌治疗针对 KRAS 突变肺癌开发新方法的需求尚未得到满足。而25-30%的肺腺癌是由于激活 KRAS 突变而产生的，个别肿瘤可能会发生 KRAS 对癌症进展过程漠不关心。众所周知，癌细胞会继续发展适应以支持肿瘤进展和转移所需的不受控制的生长和生存。新数据显示，KRAS突变癌细胞上整合素αvβ3的表达可预测哪些肿瘤肿瘤生长以及不依赖贴壁的生长（癌症的标志）仍然依赖于 KRAS 这是侵袭和转移扩散所必需的。虽然多种膜受体通过聚集在贴壁细胞中发挥作用，但整合素 αvβ3 的独特之处在于在没有细胞外基质锚定的情况下聚集和驱动信号通路的能力。初步结果表明，非贴壁细胞中的整合素 αvβ3 聚集通过使 KRAS 成瘾成为可能 KRAS 的多种功能可促进应激耐受性，包括形成巨脂质体，从而促进营养吸收和促进有利于氧化还原平衡的基因表达程序。总体目标该提案旨在定义 αvβ3 介导的 KRAS 聚类如何促进驱动 KRAS 的生存优势成瘾并促进肺癌在体内的发生、进展和转移。了解对于这一途径至关重要的分子机制将促进新疗法的设计，以利用独特的 KRAS 突变癌症的脆弱性。该 Multi-PI R01 的具体目标旨在了解细胞和分子生物学作用 αvβ3 作为 KRAS 成瘾的调节剂（目标 1 – 由 Cheresh 博士领导）并了解其与癌症的关系使用由致癌 Kras 驱动的基因工程小鼠模型进行肺癌的发生和进展（目标 2 – 由 Onaitis 博士领导）。这些发现将使针对 KRAS 的新策略的逻辑设计成为可能。成瘾细胞用于癌症治疗（目标 3 – 协作努力）。目标1：建立αvβ3体外调节KRAS功能的分子基础目标 2：确定 αvβ3 对 Kras 驱动的体内 NSCLC 的影响目标 3：利用 KRAS 成瘾来增强癌症治疗