New Investigator Grant Awarded to Kumar Pichumani

Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood brain tumor, accounting for 10% of all pediatric central nervous system tumors with a median overall survival of 10.5 months. Since DIPG tumors infiltrate brainstem and pons, they are inoperable because surgery in this location of the brain can lead into severe neurological dysfunction. No effective chemotherapy is currently available to treat DIPG tumors. Currently radiotherapy is the standard treatment of choice for newly diagnosed DIPG tumors. The hallmark of DIPG tumors is that the replacement of lysine 27 in histone H3 by methionine (H3K27M) found in ~80% of all DIPG cases. This mutation in histones H3.3 and H3.1 leads to distinct molecular subgroups with clear clinical manifestations. Unlike normal cells, cancer cells are metabolically reprogrammed to utilize multiple energy sources to meet their energy requirements for growth and proliferation. A key metabolite, α-ketoglutarate (α-KG), is shown to play an important role in tumorigenesis through epigenetic changes by changing histone methylation levels. DIPG has high levels of α-KG, which is the co-factor for DNA demethylases and histone lysine demethylases (KDM), causing histone hypomethylation and promoting tumor growth. Therefore, targeting α-KG production in DIPG tumors may be of therapeutic value. We hypothesize that DIPG tumors from these two molecular subgroups may depend on alternative nutrient sources to produce α-KG in the TCA cycle. In this proposal, we systematically investigate on the ways to decrease the production of α-KG in patient-derived DIPG cell lines and mouse model which will lead to anti-tumor effect through the use nutritional supplements (oxaloacetate and zinc) and also using commercially available metabolic inhibitors that decreases the production of α-KG. The outcome of this pre-clinical study will pinpoint key energy sources that DIPG cells depend upon to maintain elevated α-KG levels. This knowledge will lead to the identification of new targets that can be used to develop targeted therapies and testing the feasibility of new non-invasive diagnostic methods such as 11C-acetate PET and 13C-hyperpolarized MRI probing α-KG synthesis in DIPG patients.