Lung cancer is the leading cause of cancer-related deaths worldwide and there are currently no curative treatment options for patients with advanced-stage disease. Progress has been made in characterizing specific genetic alterations present in lung cancer, which in some cases has translated to therapeutic options available for patients. For instance, mutations in EGFR are found in approximately 10-15% of lung adenocarcinomas, a histological subtype of lung cancer. Patients with tumors harboring somatic mutations in EGFR are commonly treated with and respond to tyrosine kinase inhibitors (TKIs). However, the efficacy of these EGFR TKIs is undermined by the inevitable emergence of drug resistance, which develops after an average of 12 months. There are currently no approved therapeutic strategies to overcome resistance implying that these agents are not curative thus novel approaches to further improve survival for patients are needed. Recent advances in tumor immunology have informed the potential use and efficacy of immunotherapy for the treatment of several malignancies. In cancers of the lung, skin and kidney, ongoing clinical trials have shown the efficacy of therapies that modulate the immune system. An example is the blockade of the immune regulatory molecule PD-1 expressed on exhausted T cells. Using genetically engineered mouse models of EGFR mutant lung cancer, we hypothesize that the use of agents that modulate the immune microenvironment in combination with EGFR-directed therapies is an effective approach to augment the efficacy of the latter. Our hypothesis is based on: 1) published work demonstrating activation of the PD-1 pathway in mutant EGFR tumors and 2) preliminary work from our lab revealing that treatment of EGFR tumors with TKIs is not sufficient to reverse immunosuppressive features within the tumor microenvironment, including PD-1 expression on T cells. We propose to study the functional role of components of the immune system on mutant EGFR-induced tumor progression and EGFR-TKI induced tumor regression. Finally, we will determine whether the combination of EGFR-TKIs with immune- modulatory agents can be used to delay or overcome acquired drug resistance.
Lung cancer is the leading cause of cancer-related deaths worldwide and lung adenocarcinomas (LUAD) have a devastating 5-year survival rate of 16.8% (1). Targeted therapies available to treat LUADs are not curative; moreover, their efficacies are undermined by the inevitable emergence of drug resistance. This proposal will investigate the role of the immune microenvironment in LUAD progression and acquired resistance to therapies; and from our findings, we aim to establish the combined use of immunotherapy and targeted therapy as an effective approach to treat LUADs. 1. SEER data 2004-2010
