ATPS-05CHARACTERIZATION OF THE ACTIVITY OF AT13387, A NOVEL SECOND GENERATION HSP90 INHIBITOR AGAINST GLIOMAS

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates folding and stabilization of several key regulatory client proteins. In cancer, elevated Hsp90 activity is implicated in maintenance of high levels of aberrantly expressed proteins such as kinases and transcription factors making it an attractive target for treatment of several malignancies. Hsp90 inhibitors (Hsp90i) have demonstrated preclinical activity against several tumors including gliomas through downregulation of key oncoproteins inducing growth arrest and tumor cell death. AT13387 is a novel second generation orally bioavailable HSP90i which is in early phase clinical trials; however, its potential for activity against gliomas has not been studied to date. We examined the preclinical efficacy of AT13387 both alone and in combination with temozolomide (TMZ) in glioma cell lines and glioma stem-like cells (GSC). AT13387-treated glioma cells and GSC showed decreased proliferation, reduced invasion and induction of apoptosis. AT13387-treated glioma cells showed downregulation of EGFR, Akt, S6 and MAPK, key regulators of survival pathways and proliferation in gliomas. In GSC, AT13387 promoted stem cell markers downregulation and induced cell death. Of note, AT13387 treatment resulted in downregulation of MSH2, a protein of the DNA mismatch repair complex involved in TMZ-resistance and showed synergistic activity in combination with TMZ in vitro effect against glioma cells. Additionally, preliminary studies in an in vivo mouse model demonstrated that AT13387 crosses the intact blood-brain barrier. These results provide the first evidence for the activity of AT13387 against glioma both singly and in combination with TMZ and support the potential of Hsp90 inhibition as a therapeutic strategy against malignant gliomas.