The targeted inactivation of oncogene can elicit robust cell death suggesting that tumors can be "addicted" to a mutated proto-oncogene. Understanding why and predicting when tumors are addicted to oncogenes would have protean implications for the development of therapies for cancer. This would enable a more rational basis for choosing molecular targets, identify potentially new non-oncogene targets, facilitate the screening for potential agents and provide a strategy for selecting patients most likely to benefit from specific targeted therapeutic. To study oncogene addiction, we have used the Tet system to develop conditional transgenic mouse models. We have created several conditional oncogenes (MYC, RAS, BCL-2, BCR-ABL), to create transgenic mouse models of different cancers including: T-acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), osteogenic sarcoma (OS), and hepatocellular carcinoma (HCC). We have found that the consequences of oncogene inactivation are dependent upon both cellular and genetic context. Oncogene addiction involves tumor cell intrinsic and host dependent programs including the permanent loss of self- renewal or induction of cellular senescence and host-dependent programs. We are in the position to now define more generally how these mechanisms contribute oncogene inactivation induced cel death. Our hypothesis is that oncogene addiction can be modeled as a differential response between cel death and survival signaling. We will define key lynch pin gene products and pathways. Our approach will be to perform a quantitative in situ analysis using intravital microscopy and imunohistochemistry combined with a comparative proteomic and genomic analysis. We will perform these studies using different conditional oncogenes and types of cancer in different genetic contexts and then use mathematical modeling and computational biological approaches to reveal the common lynch pin genes and define their mechanistic role in oncogene addiction.

Public Health Relevance

Oncogene inactivation can elicit the phenomenon of oncogene addiction. Understanding the mechanism by which oncogene inactivation induces cell death would have broad implications for the development of therapies for cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA170378-02
Application #
8544447
Study Section
Special Emphasis Panel (ZCA1-SRLB-9 (M1))
Program Officer
Li, Jerry
Project Start
2012-09-12
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$512,190
Indirect Cost
$194,407
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Li, Y; Casey, S C; Felsher, D W (2014) Inactivation of MYC reverses tumorigenesis. J Intern Med 276:52-60
Li, Yulin; Choi, Peter S; Casey, Stephanie C et al. (2014) Activation of Cre recombinase alone can induce complete tumor regression. PLoS One 9:e107589
Ansari, Celina; Tikhomirov, Grigory A; Hong, Su Hyun et al. (2014) Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small 10:566-75, 417
Li, Yulin; Choi, Peter S; Casey, Stephanie C et al. (2014) MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. Cancer Cell 26:262-72
Casey, Stephanie C; Li, Yulin; Felsher, Dean W (2014) An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation. Immunol Res 58:282-91
Casey, Stephanie C; Bellovin, David I; Felsher, Dean W (2013) Noncanonical roles of the immune system in eliciting oncogene addiction. Curr Opin Immunol 25:246-58
Bellovin, David I; Das, Bikul; Felsher, Dean W (2013) Tumor dormancy, oncogene addiction, cellular senescence, and self-renewal programs. Adv Exp Med Biol 734:91-107
Perry, Richard H; Bellovin, David I; Shroff, Emelyn H et al. (2013) Characterization of MYC-induced tumorigenesis by in situ lipid profiling. Anal Chem 85:4259-62
Nwabugwu, Chinyere; Rakhra, Kavya; Felsher, Dean et al. (2013) In vivo imaging-based mathematical modeling techniques that enhance the understanding of oncogene addiction in relation to tumor growth. Comput Math Methods Med 2013:802512