Large cell carcinoma

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.

Lung cancer is frequently diagnosed after it has spread beyond the original tumor but not outside the chest. Patients with these “locally advanced” cancers can be treated with radiation therapy, chemotherapy and/or surgery, but unfortunately only 25% of the 60,000 patients diagnosed each year in the US are cured. The poor outcomes are largely due to an inability to give sufficient radiation to destroy the tumor without damaging surrounding vital organs. Efforts have therefore focused on increasing the ability of radiation to kill cancer cells selectively by combining radiation with specialized drugs. Unfortunately, for most patients, the available drugs increase cure rates by only about 5%. We examined the effect of deactivating each of nearly 18,000 genes on the survival of cultured lung cancer cells. The gene whose suppression resulted in the most reproducible effect was PSMA1. PSMA1 is a core component of the proteasome, the cellular machinery responsible for the recycling of proteins. Bortezomib, a drug that suppresses the proteasome, is already FDA-approved for multiple myeloma. It has been tested in lung cancer patients, but not extensively with radiation. In preparation for further clinical studies, we propose studies to determine which genetic types of lung cancer are the most resistant to radiation, and which of these may be best treated with bortezomib. Specifically, we propose to test treatment in mice that develop tumors of various genetic types commonly found in patients, and to study gene patterns in these and patient samples that may predict need for better therapies.