Small cell lung cancer (SCLC) is among the most aggressive and deadly human cancers. It represents approximately 15% of all lung cancers, and it is responsible for over 30,000 deaths in the U.S. and 200,000 deaths worldwide every year. SCLC responds to treatment in most cases, but comes back frequently and aggressively with the majority of patients dying within a year of diagnosis. SCLC is overrepresented in Veterans, is understudied, and comprises <5% of federal cancer research funding despite being the sixth leading cause of cancer death. It is not yet well understood how and why small cell lung cancer comes back resistant to chemotherapy after such a good initial response. There are multiple potential explanations all coming from the fact that there are multiple subgroups of SCLC cells living together in the same tumor. Dr. Lehman used new techniques to measure 30+ proteins in hundreds of thousands of tumor cells to identify multiple subgroups present in tumors, which change with cancer treatment. Some of these subgroups have markers similar to potential “cancer stem cells.” The goal of this proposal is to expand on this prior work by sorting these subgroups based on their replication and markers and using another technique called single-cell RNAseq to understand how these cells work and compare them to human small cell tumors obtained from a patient tissue bank. This proposal will also grow these subgroups in culture and manipulate their signaling to help identify new targeted therapies for these subgroups. This work will address the LCRP areas of emphasis on innovative strategies to understand treatment resistance, tumor heterogeneity (innovative strategies for recurrence prevention), predictive markers to assist with therapeutic decision-making, innovative strategies for the treatment of lung cancer, and progression/evolution to metastatic disease.

Dr. Lehman is a practicing VA medical oncologist who focuses his research and patient care on Veterans with SCLC. His goals is to use his background as a developmental biologist to better understand how SCLC recurs after treatment and kills patients to prevent these deaths and lead to more effective, longer lasting treatments. This award will provide support for Dr. Lehman to continue his training in new technical areas such as specific cell culturing techniques and build his body of work in the field to support continued innovative work on these subpopulations that Dr. Lehman has identified. This plan will support Dr. Lehman at the VA Nashville and VUMC as he builds new therapeutic approaches and expands these proposed experiments. The local environment has many supportive thoracic oncologists, a large number of patients and Veterans with SCLC, and a group specifically dedicated with a federal grant to modeling how SCLC grows (which works very well with Dr. Lehman’s novel techniques and research interests). This is the ideal location, setting, and time for this proposed work.

Unfortunately, this work will not immediately lead to improved patient care in SCLC; however, it will form the building blocks for a better understanding of how SCLC works, which may lead to new strategies attacking these specific subgroups of cells in patient tumors. Even confirming that these multiple subpopulations work together and that multiple cell populations that grow differently, including a rare, stem-like, cell population, would advance the field and suggest new treatment options for patient. If the initial targeting studies are successful, there are agents in clinical trials that already target these pathways, so the translational project could begin as soon as 2-3 years post completion of this work.

This work could dramatically affect how we view SCLC by allowing researcher to technically better understand SCLC at the single cell level and as groups. SCLC is overrepresented in the Veteran population, and this proposal uses tissue obtained at a VA center to help us to better understand this disease and lead to better outcomes for Veterans and their families with lung cancer.