University of Kentucky Center for Cancer and Metabolism (Pilot Project - Qingding Wang): Ketogenesis-Dependent Metabolic Reprogramming in Colorectal Cancer

Grants and Contracts Details


Metabolic reprogramming is one of the hallmarks of cancer. Altered cellular metabolism promotes tumor growth and invasiveness and limits antitumor immune response. Wnt and KRAS, frequently activated in colorectal cancers (CRCs), direct altered metabolic pathways involving enhanced glycolysis. Our studies have shown that enhancement of ketogenesis induces CRC cell differentiation and inhibits CRC cell growth. Expression of HMGCS2, a ketogenic enzyme, is down-regulated and knockdown of HMGCS2 increases glycolysis in CRC cells. Moreover, activation of Wnt/ß-catenin and KRAS inhibits ketogenesis. In addition, we found that HMGCS2 inhibits the expression of CXCL1, a cytokine which contributes to tumor immunotherapy resistance. Collectively, our studies suggest that downregulation of de novo ketogenesis is a critical step in CRC progression. The central hypothesis for our proposal is that oncogenic Wnt/ßcatenin and KRAS inhibit ketogenesis and reprogram CRC metabolism; therefore, targeting ketogenic metabolism will be an effective treatment for CRC patients harboring Wnt/ß-catenin and KRAS mutations. The following Specific Aims: (1) to determine the effect of altered ketogenesis on metabolic reprograming in CRC; (2) to determine whether targeting ketogenic metabolism in combination with immunotherapy is an effective treatment for CRC. Our proposed studies will investigate an innovative concept that oncogenic Wnt/ß-catenin and KRAS mutations reprogram CRC metabolism and render cancers dependent on decreased ketogenesis. Moreover, our studies may provide a novel precision therapy that targets ketogenic-glycolysis metabolism in CRC patients harboring Wnt/?-catenin and KRAS mutations. With this COBRE pilot award, we expect to see decreased ketogenesis, which will correlate with activated mutation of Wnt/ß-catenin or KRAS in CRCs. We further postulate that glycolysis will be repressed by increased ketogenesis in vitro and in vivo and administration of a ketogenic diet will decrease CXCL1 expression and enhance the anti-proliferative effect of anti-PD-1 treatment. With these findings, we will generate an R01 grant proposal to further determine the role of ketogenesis in Wnt and KRASmediated metabolic alterations via systematic analysis of the expression of enzymes involved in ketogenesis in CRCc. In addition, we will determine how Wnt and KRAS regulate ketogenesis. Secondly, we will determine whether the efficiency of PI3K/mTOR inhibitors is improved by administration of a ketogenic diet and whether a ketogenic diet will enhance the efficacy of anti-PD-1 therapy. The comprehensive information obtained from combination treatment in PDX models, together with mutation status data obtained in this proposed study, will provide additional mechanistic insights that will be needed to further define a patient population that will benefit from a ketogenic diet.
Effective start/end date3/1/1712/31/20


  • National Institute of General Medical Sciences


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.