HDAC8 and HDAC6 combined inhibition: a new frontier in glioblastoma treatment

GBM is the most aggressive cancer type in adults, with an extremely poor prognosis. Despite the current treatments combining surgery, radiotherapy, and chemotherapy, most patients fail to respond and show a higher mortality rate. Multiple molecular mechanisms contribute to GBM development and drug resistance, such as the receptor tyrosine kinase/Ras/phosphoinositide 3-kinase, p53-ARFMDM2, retinoblastoma, and some of the histone deacetylases (i.e. HDAC1,4,6,7,8,9,10). The specific inhibition of HDAC6 and HDAC8, both overexpressed in GBM, reduces GBM progression, but their combined inhibition could be even more promising. Indeed, they display a high degree of similarity in their active site, share common cytoplasmatic substrates and converge on the same molecular mechanisms, especially those contributing to the development of tumor resistance. In this project, we compared the effects of single HDAC6 or HDAC8 inhibitors to a combination of the two. We performed in vivo analyses, using the GBM zebrafish model zic:RAS, generated through the expression of different oncogenes in neural cells during development, and in vitro analyses in human GBM cell lines. Moreover, we tested the single or combined effects of gold standard GBM drugs (i.e. Temozolomide) with selective HDAC inhibition, and we developed a computational system for the prediction of new dual HDAC8/HDAC6 inhibitors, also testing their ability to cross the human or zebrafish blood-brain barrier. The goal of this project is to unravel HDAC6-HDAC8-regulated mechanisms underlying GBM development and to discover new inhibitors to use in pharmacological treatments. Interestingly, these findings can be translated to other tumors overexpressing HDAC6 and HDAC8, such as acute myeloid leukemia and colon cancer.