|February 16, 2022
|Targeting isocitrate dehydrogenase wild-type glioblastoma by a synthetic lethal approach
|The University of Texas Southwestern Medical Center
|Principal Investigator/Program Director
|Brain and Other Nervous System
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...