Despite our rapidly growing understanding of how oncogenes signal, relatively little is known about the underlying mechanisms that cause abrupt cell cycle arrest, cell death and tumor regression upon acutely inactivating an oncogene. This application seeks to address NIH's Provocative Question #22: Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene? We propose that acute inactivation of different oncogenes in diverse tissue types results in a common 'metabolic catastrophe.' Acute inhibition of driver oncogenes results in widespread collapse of tumor-associated metabolic reprograming. The resulting metabolic state of tumor cells can neither supply them with sufficient energy nor metabolic intermediates for anabolism resulting in a state of 'metabolic catastrophe' resulting in tumor cell death and regression of cancers.
The aims of the application seek to: 1) Use innovative hyperpolarized 13C-pyruvate imaging to visualize the earliest metabolic events associate with tumor regression. 2) We will perform global gene expression and metabolomic profiling of liver cancers driven by MYC, RAS or MYC and RAS together to define metabolic pathways altered as a consequence of acute oncogene inactivation. 3) We will compare the metabolic consequences of oncogene inactivation in diverse tissue types, including breast, lung and liver tumors to define which oncogene-regulated metabolic pathways are common across different tissue types and driver oncogenes. The overarching goal of these studies is to identify metabolic pathways critical for tumor survival, against which novel therapeutics can be developed.
A major unanswered question in cancer biology is why and how tumors regress when the initiating oncogene is acutely inhibited. This application seeks to answer this question by examining diverse metabolic changes which occur when different oncogenes are acutely inactivated. We will test the effects of inactivating two canonical oncogenes, MYC and RAS and both combined, in breast lung and liver tumor tissues. An innovative approach to study tumor formation and regression will be employed; including novel imaging technology as well as genetic and metabolic profiling of diverse tumor types. We anticipate that knowledge gained from these studies will be rapidly translated to the development of novel therapeutics to target human cancer.
|Milshteyn, Eugene; von Morze, Cornelius; Reed, Galen D et al. (2017) Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques. Magn Reson Imaging 38:152-162|
|Shin, Peter J; Zhu, Zihan; Camarda, Roman et al. (2017) Cancer recurrence monitoring using hyperpolarized [1-13C]pyruvate metabolic imaging in murine breast cancer model. Magn Reson Imaging 43:105-109|
|Kohnz, Rebecca A; Roberts, Lindsay S; DeTomaso, David et al. (2016) Protein Sialylation Regulates a Gene Expression Signature that Promotes Breast Cancer Cell Pathogenicity. ACS Chem Biol 11:2131-9|
|Camarda, Roman; Zhou, Alicia Y; Kohnz, Rebecca A et al. (2016) Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med 22:427-32|
|Louie, Sharon M; Grossman, Elizabeth A; Crawford, Lisa A et al. (2016) GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity. Cell Chem Biol 23:567-578|
|Evason, Kimberley J; Francisco, Macrina T; Juric, Vladislava et al. (2015) Identification of Chemical Inhibitors of ?-Catenin-Driven Liver Tumorigenesis in Zebrafish. PLoS Genet 11:e1005305|
|Kohnz, Rebecca A; Mulvihill, Melinda M; Chang, Jae Won et al. (2015) Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer. ACS Chem Biol 10:1624-30|
|Lim, Lionel; Balakrishnan, Asha; Huskey, Noelle et al. (2014) MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer. Hepatology 59:202-15|
|Horiuchi, Dai; Anderton, Brittany; Goga, Andrei (2014) Taking on challenging targets: making MYC druggable. Am Soc Clin Oncol Educ Book :e497-502|
|Swisher, Christine Leon; Larson, Peder E Z; Kruttwig, Klaus et al. (2014) Quantitative measurement of cancer metabolism using stimulated echo hyperpolarized carbon-13 MRS. Magn Reson Med 71:1-11|
Showing the most recent 10 out of 12 publications