Therapeutic Targeting of the Disrupted Metabolic State in DIPG
Diffuse intrinsic pontine glioma (DIPG) is the deadliest brainstem cancer in children, and significant therapeutic progress has not been made in decades. DIPG is resistant to pro-apoptotic chemotherapeutics, exhibits a profile of oxidative stress, and has disrupted cellular metabolism. Ferroptosis is an iron-dependent form of cell death mediated by the accumulation of toxic lipid peroxides. The Lyssiotis lab recently found that the disrupted oxidative/metabolic state in DIPG sensitizes these cells to ferroptotic cell death.
Project Goal: We now plan to expand and translate these studies by: (1) Determining the molecular underpinnings that lead to the profound sensitivity of DIPG cells to ferroptosis, and (2) Evaluating the anti-tumor activity of ferroptosis in human patient-derived DIPG tumor models using pharmacological and genetic approaches. Further, we will test the hypothesis that ferroptosis can be potentiated by combination treatment with other redoxdisrupting strategies, including radiation therapy. In fact, several strategies that we have found to potentiate ferroptosis in other settings could be immediately clinically deployable for DIPG, including brain penetrant inhibitors of glutathione biosynthesis. Finally, unlike cancer cells, normal cells readily tolerate inhibition of many of the redox control nodes that promote ferroptosis in DIPG cells. This suggests that a therapeutic window may exist for targeting these pathways. Results from this proposal will uncover novel druggable targets for DIPG therapy and evaluate ferroptosis as a treatment regimen that can proceed to clinical trials for DIPG patients.
Project Update 2022: We demonstrated that DIPG cells with malignant potential, the so-called stem-like cells, had high activity of respiration and cholesterol metabolism pathways. We then found that DIPG cells depend on these pathways for survival. Notably, drugs that target these pathways are safe and effectively used in millions of Americans every day. They are also brain penetrant. These features illustrate that the drugs are both safe and could be rapidly repurposed. Thus, we have most recently tested a combination of respiration inhibitor (type II diabetes drug) and a cholesterol lowering medicine (statin). We found that these are toxic to DIPG cells and have efficacy in preclinical tumor models. We are now fine-tuning the dosing strategies, and optimizing combinations with standard of care radiation therapy. Continued positive results could have an immediate impact on patients.
