Pre-clinical mouse models of SCLC to identify and test novel therapies


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Julien Sage1
1Stanford University

Abstract

Small cell lung cancer (SCLC) is a neuroendocrine subtype of lung cancer characterized by a fast growth rate, extensive dissemination, and rapid resistance to chemotherapy. Survival rates are dismal and have not significantly improved in the past few decades. Sequencing the genomes of over 100 human SCLC demonstrates universal inactivation of p53 and RB and identified inactivating recurrent mutations in NOTCH family genes (George, Lim, et al., Nature, 2015). Accordingly, we found that activation of Notch signaling in a pre-clinical SCLC mouse model dramatically reduces the number of tumors and extends the survival of the mutant mice. Thus, Notch plays a key tumor suppressive role in SCLC and strategies to re-activate Notch in SCLC tumors may be beneficial to patients.

We will present new studies focusing on mouse models on the possible role of Notch-negative and Notch-positive cells in SCLC tumors during cancer progression and in response to chemotherapy. At the histological level, SCLC tumor cells are often viewed as homogeneous. These studies and previous studies (e.g. Calbo et al., Cancer Cell, 2011 – Berns lab) identify several levels of intra-tumor heterogeneity in SCLC, which may contribute significantly to SCLC aggressive nature and resistance to therapy.