Lung cancers with neuroendocrine (NE) features, particularly small cell lung cancer (SCLC), utilize transcriptional regulatory cascades conserved from fetal nervous system development. In these lung cancers, the bHLH (basic helix-loop-helix) transcription factor human achaete scute homolog-1 (hASH1, mouse ortholog MASH1) may have a critical role in promoting tumor virulence and a primitive NE phenotype. We have shown that over-expression of this factor in transgenic airway epithelium leads to hyperplasia and enhanced carcinogenesis by SV40 Large T antigen, with NE trans-differentiation. Silencing of hASH1 in cultured SCLC cells leads to G1 cell cycle arrest. In this research proposal, we will address the question of whether hASHI/MASH1 is essential to SCLC tumorigenesis by inducibly knocking out the Mash1 gene in the context of a newly-developed mouse SCLC-like model employing an inducible knockout of both pRb and p53. We will thereby determine whether MASH1 induction is necessary for the virulent NE phenotype induced by p53 and Rb loss in this mouse model system. In additional mouse models, we will further explore the mechanisms whereby hASH1 can cooperate with individual loss of the Rb and p53 genes to promote hyperplasia, tumorigenesis, and NE transdifferentiation. Finally, we will attempt to identify transcriptional actions of MASHI/hASH1 that are critical for the aggressive growth behavior and primitive NE phenotype of SCLC. We will study candidate growth regulatory and NE genes, plus cDNA arrays in SCLC cells treated with hASHl-specific siRNA's, performing correlative studies in mouse xenografts and existing transgenic lung tumor models. The proposed studies should provide novel insights in SCLC biology and a firm basis for determining whether hASH1, and hASHl-regulated growth mechanisms, should be intensively pursued as therapeutic targets for SCLC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA070244-07A2
Application #
6725211
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
1996-06-01
Project End
2007-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
7
Fiscal Year
2003
Total Cost
$275,620
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Ball, Douglas W (2004) Achaete-scute homolog-1 and Notch in lung neuroendocrine development and cancer. Cancer Lett 204:159-69
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Sriuranpong, Virote; Borges, Michael W; Strock, Christopher L et al. (2002) Notch signaling induces rapid degradation of achaete-scute homolog 1. Mol Cell Biol 22:3129-39

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