Links between metabolism and cancer have been documented broadly, connecting obesity to increased cancer rates and alterations of cancer genes to cell metabolism. It is hypothesized that a deeper understanding of cancer cell metabolism would provide avenues toward new therapeutics that could be strategically deployed with currently available therapies to prevent or treat cancers. Proof-of-concept for targeting different metabolic enzymes such as fatty acid synthase, lactate dehydrogenase, and glutaminase has been provided with different tumor xenograft models. However, normal proliferating cells tend to use similar pathways to build cell mass and produce ATP. Normal tissues display metabolic circadian rhythms regulated by themaster clock transcription factors that are centrally synchronized via diffusible factors from the brain's suprachiasmatic nucleus that is responsive to light. Preliminary data have documented that the MYC oncogene can disrupt the cellular circadian rhythm by directly regulating components of the Clock machinery, thereby uncoupling sustained tumor metabolism from circadian regulation, while normal cells continue to display peaks and nadirs of metabolic activity. To reach the goal of understanding oncogenic circadian disruption for optimal metabolic cancer therapy timed when normal metabolic rates are lowest while cancer metabolic rates remain elevated, three aims are set in this proposal.
Aim 1. To test the hypothesis that Myc induction of Rev-erb? alters metabolism and contributes to tumorigenesis.
Aim 2. To test the hypothesis that Myc disruption of circadian gene expression alters cellular circadian metabolism as well as human cancer cell sensitivity to metabolic inhibitors in vitro.
Aim 3. To test the hypothesis that metabolic therapy administered at specific times of the day will result in better survival using a mouse model of MYC-induced hepatocellular carcinoma.
Novel approaches are required to curb the projected world-wide epidemic of cancers over the next several decades. The promise of exploiting changes in cancer metabolism for therapy is heightened by our innovation to exploit differences between the daily cyclic changes of normal cell metabolism and the high level of metabolism in cancer driven by the MYC cancer gene. This proposal innovates by considering the time component which could provide a therapeutic window such that treatments at specific times of the day would spare normal tissues while severely damaging cancer cells.
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