Targeting redox control of anaplerosis as a novel metabolic cancer therapy

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Mitochondria are small organelles (structures within cells) that provide energy and convert various nutrients into building blocks, thereby allowing cells to function, grow and divide. Because cancer cells often show elevated growth and rates of division, drugs targeting mitochondria have high potential for cancer therapy. Until recently, however, two main barriers to targeting mitochondria with drugs have limited this therapeutic approach. The first has been a lack of drugs that target the mitochondria effectively: the recent discovery of a molecule called IACS-010759 that is highly effective at targeting mitochondria has circumvented this barrier. The second barrier has been the ability of cancer cells to change the way that they use nutrients (altered metabolism) so that they can tolerate drugs targeting mitochondria. We recently reported a critical mechanism through which cells change their metabolism to bypass drugs targeting mitochondria. We therefore propose that targeting mitochondria (with IACS-010759) and targeting this new critical mechanism simultaneously may provide an effective cancer therapy. We will test this idea upon cells in the laboratory and also using dietary control or genetic tricks in mice to block the critical mechanism that allows cancer cells to bypass agents targeting mitochondria. We thereby hope to demonstrate, in principle, a new cancer therapy and we will test it upon a particularly hard-to-treat cancer - triple negative breast cancer.