Glioblastoma (GBM) remains the most common and aggressive primary malignant brain tumor in adults and holds a median survival of only 12 to 15 months. The DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) poses a significant barrier to effective treatment and renders the current standard of care chemotherapeutic, Temozolomide (TMZ), useless in approximately 50% of patients. Recently, a novel therapeutic AM-101 has been discovered to potentiate cancer cells with MGMT activation to TMZ despite their DNA repair abilities. It is hypothesized that the drug acts in one or more of three different mechanisms: MGMT deactivation, highly specific self-eating of the mitochondria (mitophagy), or non-specific self-eating of vital cellular components (autophagy). AM-101 functions as a known positive allosteric modulator of the GABA-A receptor, a known therapeutic target in glioblastoma because it functions in reverse of typical cells and can be canonically linked to all three pathways. This study rules out each of these three hypotheses as possible mechanisms of AM-101 and proves a synergistic effect with TMZ to induce apoptosis in target cells. Though the true cell signaling pathway is yet to be identified, progress has been made in narrowing molecular targets.
Chen et al. (Thu,) studied this question.