Towards more effective Glioblastoma Multiforme therapies: HDAC6 and HDAC8 combined targeting

Glioblastoma Multiforme (GBM) is the most common and lethal tumor of the central nervous system in adults, with recurrence and poor prognosis. To date, therapeutic intervention consists of surgical resection followed by radio and chemotherapy. Temozolomide (TMZ) is the standard treatment for GBM, but most patients do not respond or develop resistance. Among the aberrant pathways involved in GBM, several HDACs have been reported to be upregulated. Indeed, we previously demonstrated that the specific inhibition of HDAC6 and HDAC8 reduces GBM progression. In this work, we explore whether the combined HDAC6/HDAC8 inhibition is more effective than single inhibition, due to the different activity of the two HDACs. To accomplish this, we performed in vivo analyses using the GBM zebrafish model zic:RAS and in vitro analyses in human GBM cell lines. Moreover, we developed a computational system to predict new dual HDAC8/HDAC6 inhibitors and test their ability to cross the blood-brain barrier. Our results revealed that the combined inhibition of HDAC6 and HDAC8 elicited a stronger effect compared to the single treatments and enhanced TMZ sensitivity. This evidence supported the potential of the dual inhibition as a promising therapeutic approach for GBM and other HDAC6/HDAC8 overexpressing cancers.