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

Background: Glioblastoma multiforme (GBM) is an aggressive primary tumor of the central nervous system, characterized by high recurrence and poor prognosis. Current therapeutic strategies consist of surgical resection of the tumor area followed by radiotherapy and chemotherapy. Temozolomide (TMZ) remains the standard of care for GBM; however, over 50% of patients fail to respond and develop therapeutic resistance. Among the signalling pathways found dysregulated, HDAC6 and HDAC8 have been reported to be overexpressed. We previously demonstrated that selective HDAC6 inhibition impairs GBM progression. In this study, we investigated whether the combined inhibition of HDAC6 and HDAC8 could enhance the antitumor effects compared to single-agent treatments. Methods: To this end, we performed in vivo analyses using the zic:RAS zebrafish GBM model, in which tumor development is induced by specific oncogene expression in neural cells. In parallel, human GBM cell line T98G, characterized by a high resistant phenotype, was used as in vitro models. Cell viability, tumor growth, and autophagic flux were assessed. Results: Our results show that the combined HDAC6 and HDAC8 inhibition reduces cell viability and significantly suppresses tumor growth in zic:RAS zebrafish larvae. Moreover, combined inhibition enhances TMZ sensitivity both in vitro and in vivo. From a mechanistic perspective, HDAC6 and HDAC8 inhibition leads to impaired autophagic trafficking. To further elucidate the molecular and cellular mechanisms underlying these effects, we performed omics-based analyses to assess transcriptional changes following HDAC6 and HDAC8 inhibition. Conclusion: Overall, this integrated approach provides a powerful platform to evaluate the therapeutic potential of selective and combined HDAC6/HDAC8 inhibition and to dissect the biological mechanisms relevant to GBM progression and therapy resistance. Our findings support dual HDAC6/HDAC8 inhibition as a promising therapeutic strategy for GBM and other cancers characterized by HDAC6 and HDAC8 overexpression.