Genomic Discovery and Targeted Therapeutics in Squamous Cell Lung Cancer

鳞状细胞肺癌的基因组发现和靶向治疗

基本信息

批准号：
8716540
负责人：
Peter S Hammerman
金额：
$ 17.71万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8716540
关键词：
Accounting Biological Models Cancer Center Cancer Etiology Cancer cell line Cell Line Cells Cessation of life Clinic Clinical Clinical Trials Complement Correlative Study DDR2 gene Dana-Farber Cancer Institute Dasatinib Data Data Set Dependency Development Disease Doctor of Philosophy Drug resistance Environment Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event FDA approved FGFR1 gene FGFR2 gene FGFR3 gene Family Fibroblast Growth Factor Receptors Frequencies Genes Genomics Genotype Goals Gray unit of radiation dose Head IL6ST gene Institutes Investigation Knowledge Laboratories Learning Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Medical Oncologist Medicine Mentors Molecular Molecular and Cellular Biology Mus Mutate Mutation NF1 gene Patient Selection Patients Pharmaceutical Preparations Phosphotransferases Physicians Positioning Attribute Protein Tyrosine Kinase Proteins Recurrence Relative (related person)Research Resistance Role Scientist Series Site Squamous Cell Squamous Cell Lung Carcinoma Squamous cell carcinoma System Techniques Testing The Cancer Genome Atlas Therapeutic Therapeutic Agents Thoracic Oncology Time Toxic effect Training Activity Transgenic Animals Translations Tyrosine Kinase Inhibitor United States United States National Institutes of Health base cancer cell cancer therapy chemotherapy clinically relevant combinatorial experience gain of function mutation genome analysis improved inhibitor/antagonist kinase inhibitor medical schools meetings mutant novel novel therapeutics professor programs response standard of care therapeutic target tool treatment response tumor

项目摘要

DESCRIPTION (provided by applicant): Title Genomic Discovery and Targeted Therapeutics in Squamous Cell Lung Cancer Applicant: Peter Hammerman, MD, PhD, Dana-Farber Cancer Institute and Harvard Medical School Mentor: Matthew Meyerson, MD, PhD, Professor, Dana-Farber Cancer Institute, Harvard Medical School and Broad Institute While lung cancer remains the leading cause of cancer-related death in the United States, several recent advances in genomic characterization of lung adenocarcinomas have led to the successful use of highly effective targeted therapeutic agents in this disease, namely inhibitors of the EGFR and ALK kinases. Molecular genotyping has now become the standard of care in treating advanced lung adenocarcinoma and led to a new era of personalized medicine in lung cancer. However, these novel therapeutic strategies are largely ineffective in treating patients with the second most common type of lung cancer, squamous cell carcinoma (SCC). This proposal seeks, through a highly integrative and collaborative research strategy, to identify and therapeutically target altered proteins in squamous cell lung cancer, beginning with tyrosine kinases we have found to be altered in lung SCC, DDR2, FGFR2 and FGFR3, all of which appear to be promising therapeutic targets based on our preliminary data. This proposal seeks to further characterize the functional significance of DDR2 mutations in cellular and murine model systems and to use both existing and novel DDR2 inhibitors to target DDR2-mutant tumors. Additionally, I will study mechanisms of acquired resistance to anti-DDR2 therapy with dasatinib given the recent initiation of a clinical trial of dasatinib as a DDR2 inhibitor in lung SCCs. Furthermore, I will seek to nominate additional therapeutic targets in lung SCCs by characterizing novel mutations in FGFR2 and FGFR3 to assess their role in lung SCCs and their potential as therapeutic targets. I am a medical oncologist with a PhD and substantial prior research experience in molecular and cellular biology who is seeking K08 support for mentored research in Dr. Matthew Meyerson's laboratory. In this mentored environment, I intend to learn modern tools for genomic analysis of cancers and how to functionally validate promising genetic alterations as candidates for development of cancer therapeutics. I will also be guided by Dr. Bruce Johnson, who heads the Thoracic Oncology division at Dana-Farber, in selecting appropriate alterations and therapeutics for translation into clinical trials, as we have done with dasatinib as an inhibitor o mutated DDR2. I propose to devote a minimum of 80% of my time to a focused research program in lung SCC and will complement this with 20% of my effort dedicated to seeing patients with lung cancer in the clinic and to training activities including attendance and presentation at internal and external seminar series and meetings as well as independent coursework in the tools of translational investigation and modern genomic analysis. My ultimate goal is to become an independent physician-scientist with a tenure-track position at an academic cancer center with a research effort focused on lung cancer and the use of modern genomic techniques to identify new avenues for cancer therapeutics.

描述（由申请人提供）：鳞状细胞肺癌的标题基因组发现和靶向治疗剂申请人：彼得·哈默曼（Peter Hammerman），医学博士，博士，达纳 - 弗伯尔（Dana-Farber）癌症研究所和哈佛医学院的导师：Matthew Meyerson，医学博士，医学博士，博士尽管肺癌仍然是美国与癌症相关死亡的主要原因，但肺腺癌基因组表征的最新进展已导致在该疾病中成功使用了高效的靶向治疗剂，即EGFR和ALK激酶的抑制剂。分子基因分型现已成为治疗晚期肺腺癌的护理标准，并导致了肺癌个性化医学的新时代。但是，这些新型的治疗策略在很大程度上无效地治疗患有第二种最常见的肺癌，鳞状细胞癌（SCC）的患者。该建议通过高度综合和协作的研究策略寻求识别和治疗靶向鳞状细胞肺癌中改变的蛋白质，从酪氨酸激酶开始，我们发现在肺SCC，DDR2，FGFR2和FGFR中正在改变，这似乎是基于我们的预布数据的有希望的治疗靶标。该建议旨在进一步表征DDR2突变在细胞和鼠模型系统中的功能意义，并同时使用现有和新型的DDR2抑制剂来靶向DDR2突变肿瘤。此外，鉴于最近在肺SCC中，dasatinib作为DDR2抑制剂的临床试验开始，我将研究对抗DDR2治疗的抗药性机制。此外，我将通过表征FGFR2和FGFR3中的新型突变来评估其在肺SCC中的作用及其作为治疗靶点的潜力，从而提名肺SCC中的其他治疗靶标。我是一名医学肿瘤科医生，拥有博士学位，并且在分子和细胞生物学方面具有丰富的先前研究经验，他正在寻求K08在Matthew Meyerson博士的实验室中提供指导研究的支持。在这个受过指导的环境中，我打算学习现代工具，用于癌症的基因组分析以及如何在功能上验证有希望的遗传改变，作为癌症疗法发展的候选者。我还将受到达纳·法伯（Dana-Farber）胸部肿瘤科的负责人布鲁斯·约翰逊（Bruce Johnson）博士的指导，他选择了适当的改变和治疗剂，以转化为临床试验，就像我们以dasatinib为抑制剂O突变DDR2所做的那样。我建议将我的时间至少80％的时间用于肺SCC的重点研究计划，并将与我的20％的努力相辅相成，致力于在诊所看到肺癌的患者以及培训活动，包括内部和外部研讨会系列和会议的出勤和表现，以及独立的课程以及独立的课程工作，并在转化调查和现代种植的工具中进行独立的课程。我的最终目标是成为一名独立的医师科学家，在学术癌症中心拥有终身训练位置，研究工作的研究工作重点是肺癌，并使用现代基因组技术来识别用于癌症治疗剂的新途径。