Abstract 5755: Molecular mechanisms of small cell lung carcinoma development using preclinical mouse models

Abstract

Abstract Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer with a 5-year survival rate of less than 10%. A mouse model for human SCLC has been developed based on the fact that the RB and p53 tumor suppressor genes are mutated in more than 90% of human SCLC tumors. Rb/p53 mutant mouse lung tumors closely resemble human SCLC at the cellular and molecular levels, providing a model to probe the mechanisms underlying the development and the maintenance of SCLC in vivo. Based on preliminary evidence in a small number of human samples and tumor cell lines, we have examined the possibility that SCLC tumors may rely on the Hedgehog (Hh) signaling pathway for their growth. Hh signaling plays a key role during normal lung development and response to injury but normally has low activity in the lung epithelium. In contrast, when we crossed Rb/p53 mutant mice to Ptch1lacZ/+ reporter mice, we found that Hh signaling was active in all the SCLCs that developed. Experiments with cell lines derived from mouse tumors also indicated that the activation of Hh signaling in these cells was cell-autonomous. Constitutive activation of the Hh pathway using a mutant allele of Smo was sufficient to enhance SCLC development in vivo. Inhibition of the Hh pathway with Cyclopamine and GANT61 reduced the survival of SCLC cells in culture and of primary tumors in vivo, indicating that activation of the Hh pathway is also necessary for the expansion of these tumor cells. Thus, the Hh pathway is active in SCLC cells and plays an intrinsic role in the initiation and the maintenance of SCLC. These observations in a pre-clinical model suggest that inhibition of this signaling pathway may provide a novel means to treat SCLC patients. Emerging evidence in patients and mouse models also suggests that p130, a gene related to RB, may act as a tumor suppressor in SCLC cells. To test this idea, we used conditional mutant mice to delete p130 in combination with Rb and p53 in adult lung epithelial cells. We found that loss of p130 resulted in increased proliferation and significant acceleration of SCLC development, indicating that p130 plays a key tumor suppressor role in SCLC and providing an improved mouse model for SCLC. We are currently using this triple knock-out mouse model to identify the cell(s) of origin for SCLC as well as to elucidate the mechanisms behind the high metastatic potential of this tumor type. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5755.