Glioblastoma (GB) is the most common and aggressive brain tumor, and has some of the highest unmet needs in oncology (2.5% of cancer deaths; median overall survival: 14-16 months). Therapeutic advances have been marginal over the past decades. Management of cellular resistance cannot be addressed by treatments that involve the use of a single drug. Approaching the tumor from different angles by acting on different growth related pathways can be much more effective. Multidrug Adjunctive Cancer Treatment (MDACT) is proposed as a new treatment concept for GB, using six already-marketed non-oncology central nervous system-penetrant drugs that have evidence of ability to inhibit one or more of the identified GB growth and cell survival pathways, combined with continuous low-dose temozolomide (TMZ). Drug repurposing offers the advantage to use commercially available compounds with known safety profiles, while simultaneously unravelling molecular pathways involved in the progression of complex diseases, such as GB. In this project, we will evaluate the effects of MDACT in GB in combination with TMZ in vitro, ex vivo and in vivo. Besides paving the way for its application in the clinic, which may ultimately result in an improved patient survival, this project will lay the foundations for the establishment of a GB screening platform to evaluate future proposed regimens, as well as chemical entities.