DDEL-06. Mechanisms of emerging small molecule inhibitors for the treatment of newly diagnosed and recurrent glioblastoma

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is an aggressive and treatment-resistant primary brain malignancy with high rates of recurrence and poor survival. In recent years, small molecule inhibitors (SMIs) have gained attention as targeted therapies that disrupt specific pathways involved in tumor growth. Understanding which mechanisms of action offer the greatest therapeutic benefit remains a critical area of research. Objective: To compare the efficacy of mechanistic classes of SMIs in treating GBM and identify the best candidates for combination therapy. METHODS Publications within the past 10 years from PubMed, Scopus, Embase, Cochrane, and Web of Science were indexed to identify small molecule inhibitors (SMIs) that progressed to Phase II or III clinical trials. RESULTS The three most commonly targeted mechanisms by SMIs in GBM are tyrosine kinase inhibitors (TKIs), DNA damage response inhibitors (DDRis), and proteasome inhibitors (PIs). TKIs are further categorized by the specific kinase(s) they inhibit, DDRis by whether they target PARP1/2, and PIs by the proteasomal subunit affected. Multikinase inhibitors such as Anlotinib performed the best in regards to prolonging survival (p < 0.01) and reduced toxicity (p < 0.05) in recurrent GBM patients. Newly diagnosed GBM patients experience greatest survival outcomes when treated with Valproic Acid (p < 0.01), although Vorinostat demonstrates the lowest rate of adverse events (p < 0.05). Overall, superior survival (p < 0.01), tumor control (p < 0.001), and safety profile (p < 0.05) was seen with multikinase inhibitors used in synergy with another TKI. CONCLUSION Multikinase inhibitors 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.