Colorectal cancer (CRC) is one of the most common malignancies in the western world. One main problemin the treatment of CRC tumors is the formation of incurable metastases. Mortality is particularly associatedwith the occurrence of metastases in the liver. There is an urgent need for developing efficacious prevention ortreatment approaches for hepatic metastases of CRC. The long-term goal of my laboratory is to understand cellular metabolism under physiological andpathological conditions and to devise creative approaches for the treatment of cancer and metabolic diseases.One fundamental change in cancer is the alteration of glucose metabolism. Cancer cells exhibit high rates ofaerobic glycolysis, in which a majority of pyruvate derived from glycolysis is converted to lactate instead ofentering mitochondria for oxidative phosphorylation, even in the presence of oxygen. The cellular metabolicmode associated with aerobic glycolysis allows cancer cells to avoid complete oxidation of glucose. As a result,a significant amount of glucose is shunted to metabolic pathways for production of NADPH and metabolicintermediates, which provide the reducing agent and building blocks required for biosynthesis for proliferation.Pyruvate flux into mitochondria can be dramatically enhanced through mitochondrial uncoupling, a processthat allows protons to cross the mitochondrial inner membrane without producing ATP. As a result,mitochondrial uncouplers lead to a “futile” oxidation cycle that promotes complete oxidation of glucose. Wehypothesize that safe mitochondrial uncouplers are potent anti-cancer agents.Mitochondrial uncoupling could be induced by uncoupler protein 1 (UCP1), or by chemical uncouplers.Niclosamide is an FDA- approved anthelmintic drug that is a mitochondrial uncoupler. In our published study(Nat. Med. 20: 1263-1269), we demonstrated that niclosamide ethanolamine (NEN), a salt form of niclosamide,is primarily distributed in mouse liver, where it uncouples mitochondria. Oxyclozanide, a veterinary anthelminticdrug, is also a mitochondrial uncoupler with similar pharmacokinetic properties as NEN. The goal of the proposal is to test this novel cancer chemotherapeutic strategy and to find prototype anti-cancer agents for treating hepatic metastasis of colon cancer. Three specific aims are proposed to test ourhypothesis using pharmacological (NEN and oxyclozanide) and genetic (ectopic UCP1 expression)approaches in three hepatic metastatic CRC mouse models: (1). an immune competent tumor transplantationmodel; (2). a patient- derived xenograft (PDX) mouse model; and (3). a genetically modified mouse model(GEMM) model. A positive outcome could have significant impact on cancer chemotherapy in general. The study will alsohave high translational potential and clinical implication, in particular for treating metastatic colon cancer.
|Effective start/end date||3/15/17 → 2/28/19|
- National Institutes of Health (NIH)