Post-doctoral Fellowship Grant Awarded to Nneka Mbah

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. The Lyssiotis lab recently found that the disrupted oxidative/metabolic state in pancreatic cancer sensitizes these cells to ferroptotic cell death. Ferroptosis is an iron-dependent form of cell death mediated by lipid reactive oxygen species (ROS) that can be induced by blocking the pathways that manage lipid ROS. Applying these concepts, we found that DIPG cells are profoundly sensitive to inducers of ferroptosis. We now plan to expand and translate these studies by: (1) Testing the hypothesis that the disrupted metabolic/redox state sensitizes DIPG to ferroptosis, and (2) Evaluating the anti-tumor activity of ferroptosis in human patient-derived DIPG tumor models. Further, we will test the hypothesis that ferroptosis can be potentiated by combination treatment with other redox-disrupting strategies, including radiation therapy, the standard of care for DIPG patients. Finally, unlike cancer cells, normal cells tolerate inhibition of redox metabolism. This suggests that a therapeutic window exists for targeting these pathways. Accordingly, we will determine whether a combination of ferroptosis and radiation therapy is capable of regressing tumors using human patient-derived DIPG tumor models. In fact, several strategies that we have found to potentiate ferroptosis in other settings would be immediately clinically deployable for DIPG. Namely, pharmacological inducers of ferroptosis like BSO, which is also brain penetrant, in addition to genetic strategies that will directly promote ferroptosis will be evaluated for potential synergy with radiation treatment. 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.