This application describes a five year research career development program in the study of mechanisms of Ras transformation in a model mammalian system. The candidate is trained in Adult Oncology and has a Ph.D. in genetics. The mentor is Professor Tyler Jacks, Director of the Center for Cancer Research and Professor of Biology at the Massachusetts Institute of Technology. Dr. Jacks is a world leader in dissecting molecular pathways responsible for tumorigenesis using novel mouse cancer models. The proposed research program will provide training in developmental and cancer biology, both new fields of research for the candidate, in preparation for a career as an independent physician-scientist. ? ? Activating mutations in Ras oncogenes occur frequently in a variety of human cancers, including one third of lung adenocarcinomas. Despite several decades of intense study, the molecular basis of Ras oncogenicity is incompletely understood. The underlying hypothesis of this proposal is that the study of oncogenic Ras signaling in development will reveal important and novel mechanisms of Ras transformation, and may lead to new strategies for the prevention and treatment of Ras malignancies. The candidate recently generated mice carrying an endogenous, oncogenic allele of K-ras. These mice exhibit striking developmental defects and early embryonic lethality. This proposal seeks to test several hypotheses regarding how oncogenic K-ras and its associated negative regulators contribute to this developmental phenotype and to tumorigenesis.
Aim 1 will identify and characterize the primary developmental defects induced by oncogenic K-ras using conditional targeting strategies and tetraploid complementation.
Aim 2 will examine the role of Sprouty proteins and other Ras/MAPK antagonists in mediating the embryonic lethal phenotype associated with oncogenic K-ras.
Aim 3 will test whether induction of Ras/MAPK antagonists plays a role in Ras transformation in vitro and Ras-induced lung tumorigenesis in vivo. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA111634-01
Application #
6853816
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2005-07-06
Project End
2010-06-30
Budget Start
2005-07-06
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$135,520
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Shaw, Alice T; Winslow, Monte M; Magendantz, Margaret et al. (2011) Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc Natl Acad Sci U S A 108:8773-8
Neal, Joel W; Shaw, Alice T (2011) One allele's loss is another's gain: alterations of NKX2-8 in non-small cell lung cancer. Clin Cancer Res 17:638-9
Shaw, Alice T; Meissner, Alexander; Dowdle, James A et al. (2007) Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis. Genes Dev 21:694-707