Targeting redox control of anaplerosis as a novel metabolic cancer therapy

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.

Mitochondrial respiration provides cells with energy and enables biosynthesis of key molecules. Inhibition of mitochondrial respiration is, therefore, a promising approach for cancer therapy, particularly for tumours that have high metabolic/energetic demands. There have been two barriers to clinical application of respiration inhibitors: the lack of specificity of existing inhibitors (with consequent toxicity) and the ability of cancer cells to bypass respiration inhibition through alteration of their metabolism. The recent identification of IACS-010759, a specific and potent respiration inhibitor that is well tolerated in vivo and is in phase I clinical trials, has removed the first barrier.
We recently identified the novel metabolic pathway that enables cancer cells to alter their metabolism and bypass inhibition of respiration (Altea-Manzano et al. 2022 Molecular Cell). We hypothesise that inhibition of this novel pathway, combined with respiration inhibition, should constitute a highly effective cancer therapy, particularly for metabolically/energetically demanding tumours, such as triple negative breast cancer (TNBC) cells.
We have identified two key enzymes in the pathway for which inhibitors could be developed (MDH2 and GOT2). However, the pathway is also regulated by the redox balance of extracellular nutrients and we therefore hypothesise that dietary alteration of this balance could also be used in a cancer therapeutic setting to synergise with inhibition of respiration.
In this grant application, we propose to investigate (1) whether manipulation of extracellular redox balance can sensitise cancer cells to respiration inhibition in vitro, (2) whether dietary manipulation of redox can augment the tumour suppressive and metabolic effects of respiration inhibition upon TNBC cells in vivo and (3) whether genetic disruption of the pathway in TNBC cells can augment the tumour suppressive and metabolic effects of respiration inhibition in vivo.