Signaling Heterogeneity in Small Cell Lung Cancer

2016

Jonathan Lehman, MD, PhD

Vanderbilt University Medical Center

Nashville

Chemotherapy has been the mainstay for treatment of small cell lung cancer (SCLC)—a highly aggressive subtype of lung cancer—for the past three decades. SCLC responds well to initial treatment but inevitably comes back. No targeted therapy is currently available for patients with SCLC. Dr. Lehman is studying how SCLC becomes resistant to chemotherapy. His research will further our understanding of chemotherapy resistance and identify novel targets for SCLC treatment.

Research Summary

Small cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer. Patients do well initially, but the cancer inevitably returns with resistance to further treatment. Patient survival is dismal, with most patients dying within a year of diagnosis. Treatment has not changed or improved significantly in the last 20 years. The most likely explanation for this rapid relapse after treatment is a resistant subpopulation of cancer cells that persist after chemotherapy. Research suggests that SCLC is a very heterogeneous cancer with multiple different cancer cells that communicate which each other. This proposal expands on preliminary data that has identified multiple novel subpopulations of cells. Dr. Lehman and his team aim to better identify this diversity in human small cell by using a novel technique that can identify levels of more than 40 different cell surface markers simultaneously in individual cells. This gives them a signaling and surface marker “map.” They will then compare this map with maps from human tumors grown in mice before and after chemotherapy treatment to find out how these tumors change with treatment. Finally, they will test new treatments based on killing or disrupting specific subpopulations of cells in order to interfere with cancer growth, potentially leading to new, more specific or targeted treatment strategies for SCLC.

Technical Abstract

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 US and 200,000 deaths worldwide every year. SCLC responds to treatment but recurs frequently and aggressively, with the majority of patients dying within 12 months of diagnosis. No targeted therapies are yet available for SCLC. New strategies are needed to improve outcomes for patients with SCLC. This project will expand upon preliminary data identifying at least two distinct subpopulations of cells in SCLC cell lines and patient-derived xenografts comprising a neuroendocrine (NE) and mesenchymal-like (ML) set of cell line populations. Dr. Lehman and his team will use an innovative approach using mass cytometry, using rare earth antibody conjugates to antibody label more than 30 proteins simultaneously, including phospho and signaling proteins. This technique will establish at a single-cell resolution tumor heterogeneity and signaling in small cell lung carcinoma in multiple primary human samples as well as in patient-derived xenograft samples before and after chemotherapy treatment. This proposal aims to (1) characterize the signaling of subpopulations in human primary SCLCs at a single-cell resolution, (2) identify changes in tumor heterogeneity and in these subpopulations after chemotherapy treatment and relapse, and (3) disrupt and manipulate developmental signaling/ associated subpopulations (prototypically the HH [Hedgehog] and Notch/DLL3 pathways) to reduce tumor burden and lead to targeted rational combination therapy for SCLC.

Key words

Acquired resistance

Adenocarcinoma

Small cell lung cancer (SCLC)

Targeted therapy

Signaling Heterogeneity in Small Cell Lung Cancer

LUNGevity Foundation

CHICAGO OFFICE

BETHESDA OFFICE

MAILING ADDRESS