Targeting Immune Microenvironment Interactions in Lung Cancer Metastasis

Rationale, Relevance, and Objective: Small cell lung cancer (SCLC) is one of the subtypes of lung cancer, representing 16% of all new lung cancer diagnosis in the United States. SCLC kills more than 200,000 patients every year. Approximately 70% of patients are already diagnosed with metastasis where the tumor has spread to distant organs such as the liver and brain. These patients are initially very responsive to chemotherapy and radiation therapy, but over 95% of tumors become resistant to all therapies. Strikingly, only 5%-6% of the SCLC patients live beyond 5 years from diagnosis. There has been no improvement in the treatment options or survival rate in the past 25 years specifically for SCLC. There is an imperative need to identify new strategies to target SCLC in order to prolong lung cancer patient survival.

Some of the challenges in SCLC research include absence of targetable mutations, limited research on SCLC metastasis, absence of resected patient tissues for research, and development of rapid resistance to systemic agents. Our work proposes to identify mediators of chemoresistance, specifically in the context of metastasis using a combination of genetic mouse models of SCLC metastasis, patient-derived tissues, and xenograft models. Based on our preliminary studies, we propose three advancements in the field of SCLC research with our work. (1) Identification of a chemotherapeutic agent that more effectively kills SCLC metastasis compared to the drugs currently used in the clinic. These observations were made in SCLC mouse models and will be expanded in patient-derived models to establish the generality and translational application of our findings. (2) Defining and targeting resistance pathways in cancer cells that help them survive in distant organs in response to chemotherapy. We will use pharmacological and genetic approaches to inhibit the candidate pathways that are activated in resistant cancer cells. We will test their effect on metastasis and survival in SCLC mouse models, xenografts, and patient-derived xenografts. (3) Developing new immunotherapeutic strategies to prevent SCLC metastasis that can be used in combination with chemotherapy and targeted agents. We have identified a population of immune cells that increases in the chemoresistant metastasis in SCLC animal models. This population has special significance in breast cancer from our previous studies, where these cells contribute to chemoresistance and metastasis. Our proposed studies will identify whether the immune population can aid in the survival of SCLC metastasis cells and how can we effectively target them. In preclinical models, we will use depletion strategies to remove these immune cells in SCLC models to sensitize them to systemic therapies.

Our research specifically addresses two of the Areas of Emphasis for the Fiscal Year 2016 Lung Cancer Research Program (LCRP): (1) Understand the molecular mechanisms of initiation and progression to clinically significant lung cancer. (2) Understand susceptibility or resistance to treatment. SCLC is largely related to cigarette smoking. The rate of smoking is still considerably higher in the Veterans and military than the civilian population. Therefore, our research will benefit civilian population, military personnel, and their families. Our experimental findings will be relevant to SCLC patients who develop metastasis at any stage either at diagnosis or during the course of treatment in the future.

Principal Investigator and Team: I am a Tenure-Track Assistant Professor in the Institute for Cancer Genetics (ICG) at Columbia University. My postdoctoral work was on cancer metastasis, in the area of chemoresistance and metastasis in breast cancer. I completed my training with Dr. Joan Massague at Memorial Sloan Kettering Cancer Center (MSKCC). With the support of a K99/R00 grant from National Cancer Institute in 2013, I expanded my metastasis work on breast cancer to lung cancer. These results initiated an ongoing investigator-initiated trial on lung cancer at MSKCC. Lung cancer metastasis claims a vast majority of lives of cancer patients, which has been a driving force for me to contribute to this research. During the course of my R00 fellowship, I therefore expanded my research in the area of SCLC, a lung cancer subtype with dismal 5% 5-year survival rate. To accomplish the aims outlined in this Career Development Award, I have selected two mentors who are at the forefront of SCLC research and translational science: Dr. Charles Rudin, Chief, Thoracic Oncology, MSKCC and Julien Sage, Professor, Departments of Pediatrics and Genetics, Stanford University. My mentors have provided feedback on my research proposal and career development goals. For accelerating the progress on my scientific goals, I have formed a collaborative team with our biostatistician, immunologist, and thoracic oncologist on campus in our University. My objective is to develop myself as a lung cancer researcher at the forefront of metastasis research. Using the support of the Career Development Award, I hope to increase my visibility in the lung cancer research community, develop leadership skills, and accomplish the outlined milestones in the career development plan.