Leveraging Genetically Engineered Mouse Models of Small Cell Lung Cancer for Advanced Studies
Anna Farago, MD, PhD, Dana-Farber Cancer Institute
Massachusetts General Hospital Cancer Center,
Harvard Medical School
Small cell lung cancer (SCLC) is among the most lethal solid tumor malignancies, yet treatment outcomes have remained virtually unchanged for 30 years. New treatment paradigms are sorely needed. We have developed a series of genetically engineered mouse models of SCLC, in which conditional deletion of the tumor suppressor genes p53 and Rb1 in pulmonary epithelial cells triggers initiation of tumors that mirror the histology, molecular features, genetic alterations, and metastatic potential of human SCLC. A subset of tumors also inactivates a third tumor suppressor gene, Pten, resulting in increased PI3Kpathwaysignaling. Using in vitro and in vivo systems, we are exploring the use of targeted therapies for treating SCLC. Strategies under investigation include inhibition of the PI3K signaling pathway and combination target of rapamycin complex (TORC) and Bcl-2 family protein inhibition. We find that although PI3K pathway inhibitors are active in cell lines derived from murine SCLC tumors, inhibition of PI3K pathway signaling only minimally slows the growth of tumors in vivo; however, combining TORC inhibition with the inhibition of the antiapoptotic Bcl-2 family proteins results in potent cell death and significant tumor regression in vivo in some tumors. Using genetically engineered mice as a preclinical system, we are exploring these and other targeted therapies to develop better treatment strategies for patients with SCLC.
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