Genomic Discovery and Targeted Therapeutics in Squamous Cell Lung Cancer

申请人：Peter Hammerman，医学博士，博士，Dana-Farber癌症研究所和哈佛医学院导师：Matthew Meyerson，医学博士，教授，哈佛医学院和布罗德研究所 虽然肺癌仍然是美国癌症相关死亡的主要原因，但肺腺癌基因组特征的几个最新进展导致了高效靶向治疗药物的成功使用，即EGFR和ALK激酶的抑制剂。分子基因分型现在已经成为治疗晚期肺腺癌的标准治疗方法，并引领了肺癌个体化治疗的新时代。然而，这些新的治疗策略在治疗第二种最常见的肺癌--鳞状细胞癌(SCC)时大多无效。这项提案寻求通过高度整合和协作的研究策略，识别和治疗鳞状细胞肺癌中改变的蛋白，从我们发现在肺SCC、DDR2、FGFR2和FGFR3中改变的酪氨酸激酶开始，根据我们的初步数据，所有这些似乎都是有希望的治疗靶点。这项建议寻求进一步表征DDR2突变在细胞和小鼠模型系统中的功能意义，并使用现有的和新型的DDR2抑制剂来靶向DDR2突变的肿瘤。此外，鉴于达沙替尼作为DDR2抑制剂在肺SCCs中的临床试验最近启动，我将研究达沙替尼抗DDR2治疗获得性耐药的机制。此外，我将寻求通过表征FGFR2和FGFR3的新突变来提名肺SCC的其他治疗靶点，以评估它们在肺SCC中的作用及其作为治疗靶点的潜力。 我是一名医学肿瘤学家，拥有博士学位，在分子和细胞生物学方面有丰富的先前研究经验，正在为Matthew Meyerson博士的实验室的指导研究寻求K08支持。在这个有指导的环境中，我打算学习用于癌症基因组分析的现代工具，以及如何从功能上验证有希望的基因改变作为癌症治疗开发的候选者。我还将在Dana-Farber胸科肿瘤科负责人Bruce Johnson博士的指导下，选择适当的改变和疗法转化为临床试验，就像我们用达沙替尼作为突变DDR2的抑制剂所做的那样。我建议将至少80%的时间用于肺鳞状细胞癌的重点研究项目，并将20%的精力用于在临床上观察肺癌患者，以及培训活动，包括出席和在内部和外部研讨会系列和会议上的陈述，以及翻译研究和现代基因组分析工具的独立课程。我的最终目标是成为一名独立的内科科学家，在一个学术癌症中心担任终身教职，致力于肺癌的研究，并利用现代基因组技术来寻找癌症治疗的新途径。

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.