We have identified purine metabolism as a driver of GBM radiation resistance through de novo purine synthesis which allows GBMs to repair DNA damage from RT, and allows for tumor recurrence.  We hypothesize that a GTP signaling pathway with Rac1, PP5, and Abi-1 mediates the DNA damage response. Based on these findings we have begun a clinical trial to investigate if Mycophenolate mofetil (MMF) will help overcome this treatment resistance.

Nature Communications publication

Cancer Discovery publication

After finding links between metabolic activity and brain cancer treatment resistance, we launched an effort to directly measure cancer metabolic activity in patients. By working with neurosurgery colleagues to infuse stable isotope tracers during cancer surgeries, we have found profound metabolic rewiring in brain cancer, including an increased reliance on environmental serine.  Based on our findings we are currently developing a Phase 0/1 clinical trial of environmental serine depletion. 

Rewiring of cortical glucose metabolism preprint

We have also found connections with altered purine metabolism in Diffuse Intrinsic Pontine Gliomas (DIPG) containing the H3K27M mutation. We believe that cells with this mutation rely on purine salvage as a way to become resistance to treatment, and inhibiting this purine salvage in addition to de novo purine synthesis is a promising strategy to overcome this resistance. 

Cancer Metabolism publication

Inhibition of H3K27M-enhanced ATM signaling increases radiation efficacy in diffuse midline glioma preprint

After observing altered amino acid metabolism in a glioma patient with an IDH1 mutation, we have set out to explore the relationship between the IDH1 mutation and amino acid metabolism. Initial experiments have shown that decreasing environmental amino acids may improve treatment responses in IDH1 mutant gliomas. We look forward to continuing to explore this relationship in vivo as well as through stable isotope tracing. 

We have worked to define links between altered methionine metabolism and treatment resistance in glioblastoma. We have found that increased SAM synthesis in GBMs compared to the cortex contributes to RT resistance, and blocking SAM synthesis through methionine depletion or MAT2A inhibition helps to overcome this resistance. 

Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma preprint

We have been studying the association between myeloid cells and DNA damage repair. To study this we coculture microglia and GBM cells and have found that GBM cells repair DNA faster when cocultured with microglia. To further understand how this happens, we are analyzing the metabolites that are being secreted by the microglia and then consumed by the GBM cells, where they mediate aggressive phenotypes.