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.
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.