Assistant Professor
Department of Medicine
Division of Pulmonary and Critical Care Medicine

Project title: Development of novel therapeutic strategies to target LKB1/STK11 deficient non-small cell lung cancer

Steven M. Dubinett, MD – UCLA
Hong Wu, MD, PhD – UCLA

Multidisciplinary Expertise:
Translational cancer research, signal transduction, metabolism, lung carcinogenesis, genetically engineered mouse models of lung cancer, micro PET-CT imaging

Project Description:
My project focuses on identifying and testing novel therapies for the treatment of early stage LKB1-deficient lung tumors. The LKB1 tumor suppressor functions as a master regulator of cellular growth, metabolism and survival.  Importantly, the LKB1 gene is frequently mutated in ~35% of non-small cell lung cancer (NSCLC) however, the molecular mechanisms driving tumor growth following LKB1 mutations are poorly understood and to date there are no therapies that target LKB1-deficient lung cancer.  As more targeted therapeutics for NSCLC are needed, I explored use of biguanides, traditionally used to treat diabetes, as metabolic stress agents to target LKB1-deficient lung tumors.  At a cellular level, LKB1-deficient tumor cells are unable to respond to energy stress and selectively undergo increased apoptosis following treatment with metabolic stress agents such as biguanides. The selective sensitivity of LKB1-deficient tumors to metabolic stress presents an Achilles heel to exploit and opens a therapeutic window from which to target LKB1-deficient cells. Additionally, loss of the LKB1 gene results in elevated mTOR signaling that results in increased tumor growth and proliferation.  My project will investigate the use of biguanides (metformin or phenformin) in combination with targeted mTORC1 inhibitors (rapamycin or INK128) for the treatment of LKB1-deficient NSCLC.  I will perform preclinical studies using genetically engineered mouse models of lung cancer to assess the efficacy these novel drug combinations in vivo.  Using micro 18FDG-PET and bioluminescence imaging in combination with detailed immunohistochemical and biochemical analysis I will dissect the molecular signaling pathways driving tumor growth and survival in LKB1-deficient lung tumors. With this multifaceted approach I aim to uncover novel pathways that can be exploited therapeutically in LKB1-deficient tumors. My overarching goal is to identify new, clinically relevant therapeutic strategies to treat patients with NSCLC harboring LKB1 mutations.