DDDR-09. Novel small molecule inhibitor candidates for the treatment of newly diagnosed and recurrent glioblastoma

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive primary CNS neoplasm, presenting with high recurrence, treatment resistance, and mortality. Small molecule inhibitors (SMIs) have been on the rise as innovative targeted therapies, crossing the blood-brain-barrier and inhibiting key tumorigenesis pathways. Objective: To compare the efficacy of various mechanistic classes of SMIs–the most promising being tyrosine kinase inhibitors (TKIs), DNA damage response (DDR) inhibitors (DDRis), and proteasome inhibitors (PIs)–in treating GBM. METHODS We indexed articles from the last 10 years to identify SMIs that reached Phase II or III clinical trials using PubMed, Scopus, Embase, Cochrane, and Web of Science. RESULTS TKI Anlotinib—targeting VEGFR, PDGFR, and FGFR—demonstrates the highest overall survival (OS, p < 0.05), progression-free survival (PFS, p < 0.01), overall response rate (ORR, p < 0.001), and lowest rate of serious adverse events (SAEs, p < 0.05) among TKIs, the most studied class of SMIs. For newly diagnosed GBM, the most frequently used SMI is DDRi Valproic Acid (VPA) which prolongs OS (p < 0.001) and PFS (p < 0.01), though DDRi Vorinostat demonstrates superior ORR (p < 0.01) and lower SAE (p < 0.05). Overall, VPA best prolongs survival (p < 0.01), while Anlotinib offers the best tumor control (p < 0.001) and safety profile (p < 0.01). SMIs are commonly used in combination therapies, most often with another SMI or temozolomide (TMZ), with DDRis performing best while in combination with TMZ (p < 0.01). CONCLUSION SMIs such as Anlotinib and VPA carry great potential as additions to the existing GBM treatment regimen by providing synergistic tumor selectivity, limited adverse effects, greater treatment compliance, and improved prognosis. These findings highlight the need for continued preclinical and translational research to elucidate underlying mechanisms and support the design of biomarker-driven clinical trials evaluating SMI-based combination therapies in GBM.