Scientific Objective and Rationale for the Proposed Project: This proposal aims to identify novel therapeutics for the treatment of early stage lung cancer harboring mutations in the LKB1 tumor suppressor gene. Our goal is to explore the use of biguanides (metformin or phenformin) in combination with targeted therapeutics as anti-cancer agents to treat LKB1-deficient lung tumors. Through the use of state-of-the-art imaging and molecular analysis in human and mouse models of lung cancer, we aim to identify new and more effective therapies and to identify the causes of lung cancer development, which will pave the way for future development of drugs that prevent lung cancer or cure it at an early stage of development.

Each year, approximately 220,000 people are diagnosed with lung cancer, and the disease accounts for 27% of all cancer-related deaths. The LKB1 tumor suppressor is a master gene regulating cell growth, metabolism, and survival, and it is mutated and inactivated in ~30% of sporadic non-small cell lung cancers (NSCLC). In cells defective for LKB1, metabolic stress is not appropriately sensed and energy balance is not efficiently restored, providing an Achilles heel to target in tumors with this genetic mutation. Currently, there are no targeted therapies to treat tumors with LKB1 mutations; therefore, we explored the use of metabolic drugs to be used as anti-cancer agents to target lung tumors with LKB1 mutation. We focused on a class of drugs known as biguanides, including metformin, which were historically used to treat metabolic disease and are currently taken daily by approximately 120 million patients to manage their diabetes. As targeted therapeutics for LKB1 mutant tumors are needed, we explored the use of biguanides to induce metabolic stress and cell death in LKB1 mutant lung tumors. Treatment of genetically engineered mouse models of NSCLC with the biguanide phenformin as a single agent reduced tumor size, induced tumor cell death, and prolonged survival in mice whose tumors bear Lkb1 mutation. This suggests phenformin as a metabolism-based cancer therapeutic selectively targets LKB1-deficient tumors. However, phenformin was not curative as a single agent, thus we must identify additional pathways to target to prevent the development of LKB1 mutant lung cancer. We have identified several pathways, including the mTORC1 and autophagy pathways that LKB1-deficient tumors depend on for growth and survival. Therefore, combining biguanide treatment with an inhibitor against the mTORC1 or autophagy pathway provides a rational therapeutic strategy to selectively kill LKB1-deficient lung tumors.

Ultimate Applicability of the Research: The goal of our research is to benefit a large population of NSCLC patients diagnosed with early stage lung cancer that is positive for LKB1/STK11 gene mutations. Using metabolism drugs, like metformin, that are already FDA-approved and widely prescribed for the treatment of diabetes, we aim to re-purpose this class of drugs for the treatment and possible prevention of lung cancer. Further, by combining metabolic therapies with targeted therapies, such as Rapamycin, that are in clinical trials, we aim to develop new and more effective strategies for lung cancer prevention and treatment in patients with LKB1 mutation. By targeting LKB1 mutations, we intend to individualize prevention and therapy for patients and provide an inexpensive and safe regimen that will prevent lung cancer altogether or treat it at an earlier stage when cure is more likely. The projected time to achieve a clinically relevant outcome is approximately 5 to 6 years following analysis of these preclinical trials in human and murine NSCLC tumor models and following by enrollment of NSCLC patients with LKB1 mutations in Phase I and II clinical trials.

Likely Contributions of this Study to Advancing the Field of Lung Cancer Research:

The research we propose to conduct will advance lung cancer research in three areas.

(1) Development of novel and safe therapies for treatment of early stage lung cancer with LKB1 mutation;

(2) Identification of new protein targets for the development of specific inhibitors to treat lung tumors with LKB1 mutations;

(3) Map the molecular signals that drive growth of different lung tumor subtypes, so clinicians and pathologists can coordinated more effective therapeutic strategies based on the tumor subtype and mutational profile.