Mechanistic Determination of KRAS Lung Cancer Regression upon CRAF Suppression

CRAF 抑制后 KRAS 肺癌消退的机制测定

基本信息

批准号：
10618771
负责人：
Victoria Wang
金额：
$ 24.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618771
关键词：
Ablation Accounting Advisory Committees Affinity Alleles Apoptosis Apoptotic Area BRAF gene Binding Biochemical Biology Biometry CD8-Positive T-Lymphocytes Cancer Biology Cancer Etiology Cancer Patient Cancer cell line Cell model Cells Cessation of life Clinical Clinical Trials Collaborations Combined Modality Therapy Data Data Reporting Databases Development Disease Drug Targeting Environment FGF1 gene Family member Feedback Funding Genetic Genetically Engineered Mouse Goals Growth Factor Guanosine Triphosphate Human Immune Immunologic Techniques Immunologics Immunology Individual Induction of Apoptosis Institution KRAS2 gene Literature Lung Neoplasms MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Mentors Mentorship Modeling Molecular Mutation Non-Small-Cell Lung Carcinoma Oncogenic Operative Surgical Procedures PIK3CG gene Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phosphotransferases Principal Investigator Production Proteins Proteomics Publishing RAF1 gene Reporting Research Research Personnel Resected Resources Secondary to Sequence Alignment Signal Transduction System T cell infiltration T-Lymphocyte Technical Expertise Testing The Cancer Genome Atlas Training Translational Research Tumor Cell Line United States United States National Institutes of Health Work autocrine cancer regression career career development cytokine derepression experience improved inhibitor innovation insight knock-down laboratory experience lung tumorigenesis meetings mortality mutant novel novel strategies novel therapeutic intervention novel therapeutics pharmacologic potential biomarker predicting response programs rational design resistance mechanism systemic toxicity transcriptome sequencing translational cancer research tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. KRAS is a major oncogenic driver of this disease and found in ~ 30% of all NSCLCs. Unfortunately, efforts to develop drugs that target mutant KRAS proteins have largely been unsuccessful, since both single agent inhibition of effector pathways downstream of KRAS or combinations have proven to be ineffective. Thus, developing novel therapies for KRAS-driven NSCLC remains an area with a critical unmet need. The overarching goal of this proposal is to dissect the mechanistic underpinning of how genetic ablation of CRAF induces regression of KRAS-driven NSCLC. We have generated a KRAS-driven, human NSCLC cell line with inducible CRAF expression that undergoes apoptosis upon CRAF knockdown. This proposal utilizes this system, along with biochemical and immunological techniques, to 1) identify the domain(s) of CRAF responsible for mediating tumor regression, 2) determine the downstream effectors necessary for tumor regression, and 3) characterize the changes within the tumor microenvironment upon CRAF loss. Improved mechanistic understanding of this phenomenon and successful execution of these aims will lead to novel strategies for targeting KRAS-driven lung cancers, either as monotherapy or rationally-designed combination therapy, as well as potential biomarkers predictive of response. Dr. Victoria Wang is mentored by Dr. Frank McCormick, a world expert in RAS signaling, and will also benefit from an advisory committee comprised of Dr. Dean Sheppard, Dr. David Carbone, Dr. Matthew Krummel, and Dr. Shiva Malek, who will collectively provide mentorship, collaboration and expertise in cancer biology, signaling, immunology, and lung cancer translational research. Dr. Wang has also formulated a comprehensive 5-year training plan that will leverage the outstanding resources available at UCSF (ranking second in NIH funding among all institutions), incorporating laboratory training, didactic coursework, scientific meetings and professional development opportunities that will assist her in achieving her scientific and career goals of developing into an independent, translational lung cancer investigator.

项目概要非小细胞肺癌（NSCLC）是全球癌症死亡的主要原因。 KRAS 是一个主要这种疾病的致癌驱动因素，约 30% 的非小细胞肺癌中都有发现。不幸的是，开发药物的努力目标突变 KRAS 蛋白基本上不成功，因为单药抑制效应子 KRAS 下游途径或组合已被证明是无效的。因此，开发新颖的 KRAS 驱动的非小细胞肺癌的治疗仍然是一个亟待满足的领域。本次活动的总体目标是提议是剖析 CRAF 基因消融如何诱导退化的机制基础 KRAS 驱动的 NSCLC。我们已经生成了 KRAS 驱动的人类 NSCLC 细胞系，具有可诱导的 CRAF CRAF 敲低后发生细胞凋亡的表达。该提案利用了该系统，以及生化和免疫学技术，1) 识别负责介导的 CRAF 结构域肿瘤消退，2) 确定肿瘤消退所需的下游效应器，以及 3) 表征 CRAF 丢失后肿瘤微环境的变化。提高对此的机械理解现象和这些目标的成功执行将带来针对 KRAS 驱动的新策略肺癌，无论是单一疗法还是合理设计的联合疗法，以及潜在的预测反应的生物标志物。 Victoria Wang博士的导师是世界医学专家Frank McCormick博士。 RAS 信号传导，还将受益于由 Dean Sheppard 博士、David 博士组成的咨询委员会 Carbone、Matthew Krummel 博士和 Shiva Malek 博士将共同提供指导和合作以及癌症生物学、信号传导、免疫学和肺癌转化研究方面的专业知识。王医生有还制定了全面的 5 年培训计划，将利用现有的优秀资源 UCSF（在 NIH 资助的所有机构中排名第二），结合了实验室培训、教学课程作业、科学会议和专业发展机会将帮助她实现她的目标发展成为一名独立的转化性肺癌研究者的科学和职业目标。