TRTH-03. CYTO-MITO™ - A NOVEL CLASS OF DUAL-ACTING HSP90 INHIBITORS FOR THE TREATMENT OF GLIOBLASTOMA

Abstract

Glioblastoma (GBM) is a highly invasive and aggressive primary brain tumor and is considered one of the deadliest forms of cancer. Despite aggressive therapies, half of GBM patients die within 15 months after diagnosis and only 2% survive more than 5 years. Therefore, effective treatments for GBM represent an urgent unmet medical need. Genetic profiling of glioma has shown multiple oncogenes critical for cell-signaling are not only mutated and/or amplified but can also circumvent the otherwise clinically promising targeted therapeutics. Therefore, a therapy that can simultaneously suppress multiple cell-signaling oncogenes using a single agent may be a more effective therapeutic strategy for GBM. Cytosolic Hsp90 facilitates GBM tumor cell growth and survival by assisting in the proper folding and active conformation maintenance of many oncoproteins. The mitochondrial Hsp90 homolog, TNF Receptor Associated Protein-1 (TRAP1) is also elevated in GBM tumors and participates in pleiotropic signaling circuitries of organelle integrity and cellular homeostasis. Thus, dual-acting Hsp90/TRAP1 inhibitors benefit from the advantage of simultaneously disrupting a multitude of cancer-promoting pathways and have successfully demonstrated anti-tumor effectiveness against a number of glioma cell lines and in vivo preclinical models. Taken together, these data support concomitant inhibition of cytosolic Hsp90 and the mitochondrial TRAP1 using a single agent represents a novel “double-pronged” approach for effective GBM treatment. Plex has discovered dual-acting (Hsp90/TRAP1) inhibitors demonstrating low sub-micromolar efficacy in multiple clinically relevant Mayo Clinic GBM patient-derived cell lines. Consistent with sub-micromolar efficacy, our compounds caused ≥50% suppression in EGFR and Akt1 levels in these cell lines. In addition, the compounds induced mitochondrial dysfunction, both in cells and in isolated mitochondria. Preliminary studies also show, a compound in our Hsp90/TRAP1 inhibitor series achieved effective concentrations in normal rat brains, indicating effective blood brain barrier crossing. This work was supported by National Institutes of Health grant (1R43GM090383).