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.

Public Health Relevance

This proposal seeks to use modern genomic techniques to define genetic alterations found in squamous cell lung cancers, the second most common type of lung cancer, in order to identify alterations which are specific to cancer cells and which could be targeted by specific drugs. The focus will be on laboratory characterization of candidate alterations in DDR2 and the FGFR family kinases as potential therapeutic targets. This approach has been successful in lung adenocarcinoma, the most common type of lung cancer, in which patients who have specific genetic alterations in their tumor are now successfully treated with relatively non-toxic molecularly targeted medications instead of chemotherapy. I plan to use modern-day genome analysis techniques to expand our knowledge about squamous cell lung cancers to allow for the development of new cancer therapies which will hopefully be more effective and less toxic than current chemotherapies for patients with this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA163677-02
Application #
8531888
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$177,120
Indirect Cost
$13,120
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Yard, Brian D; Adams, Drew J; Chie, Eui Kyu et al. (2016) A genetic basis for the variation in the vulnerability of cancer to DNA damage. Nat Commun 7:11428
Campbell, Joshua D; Alexandrov, Anton; Kim, Jaegil et al. (2016) Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet 48:607-16
Xu, Chunxiao; Buczkowski, Kevin A; Zhang, Yanxi et al. (2015) NSCLC Driven by DDR2 Mutation Is Sensitive to Dasatinib and JQ1 Combination Therapy. Mol Cancer Ther 14:2382-9
Li, Yvonne Y; Hanna, Glenn J; Laga, Alvaro C et al. (2015) Genomic analysis of metastatic cutaneous squamous cell carcinoma. Clin Cancer Res 21:1447-56
Tanizaki, Junko; Ercan, Dalia; Capelletti, Marzia et al. (2015) Identification of Oncogenic and Drug-Sensitizing Mutations in the Extracellular Domain of FGFR2. Cancer Res 75:3139-46
Terai, Hideki; Tan, Li; Beauchamp, Ellen M et al. (2015) Characterization of DDR2 Inhibitors for the Treatment of DDR2 Mutated Nonsmall Cell Lung Cancer. ACS Chem Biol 10:2687-96
Gandara, David R; Hammerman, Peter S; Sos, Martin L et al. (2015) Squamous cell lung cancer: from tumor genomics to cancer therapeutics. Clin Cancer Res 21:2236-43
Rusan, Maria; Li, Yvonne Y; Hammerman, Peter S (2015) Genomic landscape of human papillomavirus-associated cancers. Clin Cancer Res 21:2009-19
Wang, J; Mikse, O; Liao, R G et al. (2015) Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells. Oncogene 34:2167-77
Seiwert, Tanguy Y; Zuo, Zhixiang; Keck, Michaela K et al. (2015) Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res 21:632-41

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