Mechanistic Determination of KRAS Lung Cancer Regression upon CRAF Suppression

CRAF 抑制后 KRAS 肺癌消退的机制测定

• 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
• 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

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.

项目摘要 非小细胞肺癌（NSCLC）是世界范围内癌症死亡的主要原因。KRAS是一个主要的 这种疾病的致癌驱动因素，发现在所有NSCLC的约30%。不幸的是，开发药物的努力 靶向突变型KRAS蛋白在很大程度上是不成功，因为两种单一药剂抑制效应子 KRAS下游途径或组合已被证明是无效的。因此，开发小说 KRAS驱动的NSCLC的治疗仍然是一个关键的未满足需求的领域。这个项目的首要目标是 建议是剖析CRAF基因消融如何诱导CRAF消退的机制基础， KRAS驱动的NSCLC。我们已经产生了KRAS驱动的具有诱导型CRAF的人NSCLC细胞系， CRAF敲低后发生细胞凋亡。本提案利用该系统，沿着 生物化学和免疫学技术，以1）鉴定CRAF的结构域，其负责介导 肿瘤消退，2）确定肿瘤消退所必需的下游效应物，和3）表征 CRAF丧失后肿瘤微环境的变化。提高对这一点的机械理解 现象和成功执行这些目标将导致针对KRAS驱动的新战略 肺癌，无论是作为单药治疗或合理设计的联合治疗，以及潜在的 生物标志物预测反应。维多利亚王博士是指导博士弗兰克麦考密克，世界专家， RAS信号，并将受益于一个咨询委员会组成的博士院长谢泼德，博士大卫 Carbone，Matthew Krummel博士和Shiva Malek博士，他们将共同提供指导， 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。王博士 还制定了一项全面的五年培训计划，将利用 加州大学旧金山分校（在所有机构中排名第二的国家卫生研究院的资金），结合实验室培训，教学 课程作业，科学会议和专业发展机会，这将有助于她实现她的 发展成为一个独立的，翻译肺癌研究者的科学和职业目标。