Identifying Tumor Genomic Changes In Lung Cancers

The treatment of lung cancer has been revolutionized by the discovery of specific targeted therapies such as erlotinib or gefitinib for EGFR-mutated lung cancer and crizotinib for ALK-translocated lung cancer. These successes have taught us that lung cancer is not just one disease, but a multitude of different diseases, best defined by the specific tumor genetic changes that are driving tumor growth and that can serve as targets for therapy. At Massachusetts General Hospital, we have been performing tumor genetic testing via SNaPshot, a panel of known oncogenic mutations, since 2009. We have found that approximately 40% of our patients do not have an identifiable mutation. For these patients, identifying what tumor genetic changes are driving their cancer will be critical to develop effective targeted therapy. This proposal therefore is focused on those patients who did not have an identifiable tumor mutation, with the hope that we can discover new targets for effective therapy. We plan to do this by two methods: First, we will perform whole exome sequencing, i.e. sequencing the coding regions of the tumor genome, on the tumors of patients who did not have any identifiable tumor mutations. Second, we will screen for chromosomal rearrangements involving tyrosine kinases. Tyrosine kinases are of particular interest in cancer, as they play a role in cell growth and proliferation, and more importantly are potentially “druggable.” With this two-pronged approach, we hope to identify novel tumor-related genetic changes that will lead to new targeted therapies for lung cancer.

TECHNICAL INFORMATION
Targeted therapies such as erlotinib or gefitinib for EGFR-mutated lung cancer and crizotinib for ALK-translocated lung cancer can yield remarkable responses and significant clinical benefit. Other mutations in genes such as K-RAS, BRAF, and PI3K, among others, are also being actively investigated as targets of new drugs in clinical trials. However, a substantial number of patients (~40%) have no mutations when tested with a panel of known oncogenic mutations. The aim of this research proposal is to identify novel somatic genomic alterations in lung cancer, using an existing tumor bank of lung cancer cases with known clinical and tumor genetic information. We will focus on those lung cancers that are known to be wildtype on SNaPshot and ALK FISH (fluorescence in situ hybridization) (i.e., negative for over 50 tested oncogenic mutations), and perform both deep sequencing of exomes and a comprehensive search for translocations involving kinases. We believe that this effort will identify novel tumor genomic changes that can be targets for therapy.