Targeting fatty acid oxidation for treatment of cancer, including AML, prostate, breast and colon cancers
Several cancers are characterized by slow glycolysis and rely on non-glycolytic pathways such as fatty acid oxidation (FAO) as their main source of energy. While dependency of cancer cells on FAO has been known, the underlying mechanistic understanding has yet to be translated into clinical benefits. As described in a paper published in Molecular Cell, Dr. Haigis and her group at Harvard Medical School have identified Prolyl hydroxylase 3 (PHD3) as a regulator of a molecular pathway that drives a cancer cell's dependency on FAO as its primary energy source. Re-expression of PHD3 in cancer cells led to activation of acetyl-coA carboxylase 2 (ACC2), reduction of tumor cell proliferation and significantly higher survival rates among animals injected with PHD3-overexpressing AML cells compared to animals injected with their PHD3-low counterparts. Furthermore, pharmacological intervention with FAO inhibitors etomoxir or ranolazine led to significant cell death in PHD3-low leukemia cells. This discovery suggests that low PHD3 expression level is an indicator of the sensitivity of cancer to perturbations of FAO pathways and opens a path for development of novel cancer therapies with readily available diagnostic tools enabling identification of responder patient populations whose tumors may be sensitive to FAO inhibitors. The Haigis lab is interested in a collaboration with an industry partner to advance this program.
Intellectual Property Status: Patent(s) Pending