The targeted repair or inactivation of damaged proto-oncogenes (oncogenes) may be a specific and effective treatment for neoplasia. My long-term goal is to understand bow oncogenes induce and maintain tumorigenesis. My strategy has been to generate a conditional transgenic model system using the tetracycline regulatory system to investigate how oncogene activation causes tumorigenesis and when continued activation is required to maintain a tumorigenic phenotype. I have focused on investigating how over-expression of the MYC proto-oncogene causes tumorigenesis. My hypothesis is that the mechanism by which MYC induces tumorigenesis will define when its continued expression is required to maintain a tumorigenic phenotype, and thus, when its inactivation will induce tumor regression. Recently I have shown that MYC-induced tumors regressed upon MYC inactivation (see Appendix, Feisher and Bishop, Molecular Cell, 1999). From these results, I conclude that there are circumstances when the inactivation of MYC can cause tumor regression. Now, I propose experiments to address the following three specific aims:(1) 1 will determine how MYC activation induces tumorigenesis in hematopoietic cells by influencing the cell cycle, genomic stability and apoptosis and how other oncogenes (p53-I-, p]9ARF-/-, ROAS, BCL2) cooperate with MYC to influence these same parameters. (2) I will determine how MYC inactivation causes tumor regression, if MYC re-activation permits tumor relapse, and if cooperating oncogenic events (p53-I-, p19ARF-/-, RAS, BCL2 ) prevent regression or promote relapse. (3) I will determine how MYC maintains a tumorigenic phenotype by examining if (MYC family members (N-, L-MYC), S-MYC or MYC mutants defective for specific functional domains or MYC 's transcriptional targets (ODC, eIF-4E, TERT) can functionally replace MYC. I will attempt to identify novel genes that can functionally replace MYC to maintain in part or whole its neoplastic phenotype. The results obtained from these studies will be useful in determining how MYC causes tumorigenesis and defining when the inactivation of MYC is likely to be effective in the treatment of human neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089305-03
Application #
6633901
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
2001-06-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$364,704
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Casey, Stephanie C; Tong, Ling; Li, Yulin et al. (2016) MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352:227-31
Casey, Stephanie C; Amedei, Amedeo; Aquilano, Katia et al. (2015) Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin Cancer Biol 35 Suppl:S199-S223
Shroff, Emelyn H; Eberlin, Livia S; Dang, Vanessa M et al. (2015) MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc Natl Acad Sci U S A 112:6539-44
Casey, Stephanie C; Vaccari, Monica; Al-Mulla, Fahd et al. (2015) The effect of environmental chemicals on the tumor microenvironment. Carcinogenesis 36 Suppl 1:S160-83
Yetil, Alper; Anchang, Benedict; Gouw, Arvin M et al. (2015) p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia. Oncotarget 6:3563-77
Gabay, Meital; Li, Yulin; Felsher, Dean W (2014) MYC activation is a hallmark of cancer initiation and maintenance. Cold Spring Harb Perspect Med 4:
Li, Y; Casey, S C; Felsher, D W (2014) Inactivation of MYC reverses tumorigenesis. J Intern Med 276:52-60
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
Bisikirska, B C; Adam, S J; Alvarez, M J et al. (2013) STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma. Oncogene 32:5283-91

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