Glioblastoma multiforme (GBM) classified by wild-type isocitrate dehydrogenase (IDHWT) represents 90% of highly malignant GBM with few effective treatments available. Identification of new molecular targets and development of novel effective therapies are the urgent medical needs to eliminate this deadly disease.

Through an unbiased screen, we found that deficiency of the enzyme branched-chain amino acid transaminase 1 (BCAT1) selectively sensitized IDHWT GBM cells to cell-permeable alpha-ketoglutarate (AKG)-induced cell death. Combination treatment of AKG and a BCAT1 inhibitor gabapentin also induced synthetic lethality of IDHWT GBM in vitro and in vivo, suggesting that BCAT1 inhibition (BC...

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Glioblastoma multiforme (GBM) classified by wild-type isocitrate dehydrogenase (IDHWT) represents 90% of highly malignant GBM with few effective treatments available. Identification of new molecular targets and development of novel effective therapies are the urgent medical needs to eliminate this deadly disease.

Through an unbiased screen, we found that deficiency of the enzyme branched-chain amino acid transaminase 1 (BCAT1) selectively sensitized IDHWT GBM cells to cell-permeable alpha-ketoglutarate (AKG)-induced cell death. Combination treatment of AKG and a BCAT1 inhibitor gabapentin also induced synthetic lethality of IDHWT GBM in vitro and in vivo, suggesting that BCAT1 inhibition (BCAT1i) and AKG combination is a novel and non-toxic approach to kill IDHWT GBM. However, the underlying mechanism remains obscure.

In the current project, we will determine the therapeutic potential of BCAT1i & AKG combination in the in vitro and in vivo clinically relevant IDHWT GBM models and its underlying mechanisms. The multi-pronged approaches we proposed ensure a direct clinical relevance and a strong scientific rigor of this project. To accomplish the proposed project, we have assembled a multidisciplinary research team with complementary expertise, which includes a principal investigator Dr. Weibo Luo, who has expertise in metabolism and GBM research, and three outstanding collaborators including a leading expert in cancer metabolism Dr. Ralph DeBerardinis, an expert in neurobiology Dr. Yingfei Wang, and a pathologist Dr. Kimmo Hatanpaa at UT Southwestern.

Successful completion of this project will define and characterize a novel metabolic vulnerability of IDHWT GBM and to identify a non-toxic and effective approach to kill IDHWT GBM. Therefore, this project will provide a paradigm shift in IDHWT GBM therapy, leading to reduced mortality of patients with this very aggressive and deadly disease.

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