P18.14.B THE COMBINATION OF TEMOZOLOMIDE AND PERIFOSINE SYNERGISTICALLY INHIBITS GLIOBLASTOMA GROWTH

Abstract BACKGROUND Glioblastoma is the primary brain tumor of the central nervous system, with a median survival of less than 15 months. Despite its approval by the FDA in 2005 as a first-line treatment for glioblastoma, TMZ has exhibited limited efficacy primarily due to the inherent heterogeneity and rapid emergence of resistance. Therefore, effective drugs with low toxicity are urgently to be developed or combined for glioblastoma treatment. MATERIAL AND METHODS The effects of AKT expression on the prognosis of TMZ were analyzed in the Chinese Glioma Genome Atlas (CGGA) database. CCK-8 and plate cloning experiments evaluated the effects of TMZ and perifosine on glioblastoma cell proliferation. SynergyFinder APP calculated the Synergy Score. RNA-seq was used to analyze the possible mechanism pathways and verified by Western blot and alkaline comet assay. Apoptosis was detected by Flow cytometry and Western blot after TMZ and perifosine treatment. Finally, the antitumor activity of the drug was detected in glioblastoma xenografted nude mice. RESULTS Bioinformatics analysis showed a poor prognosis of high-expression AKT in TMZ-treated glioblastoma patients. Therefore, we hypothesized that the combination of TMZ with AKT inhibitor perifosine can improve the sensitivity of TMZ and may be an effective treatment for glioblastoma. Perifosine stands as the pioneering allosteric AKT inhibitor in clinical development, showcasing commendable safety and notable permeability across the blood‒brain barrier. Consequently, we opted for the combination of TMZ and perifosine to investigate their collective impact on glioblastoma treatment at the preclinical stage. The ZIP Synergy scores for the combined treatment in U87MG and U251 were 20.349±1.92 and 14.766±1.33, respectively. We found that the combination of TMZ and perifosine synergistically inhibits glioblastoma. This co-treatment significantly decreases BRCA1 expression, leading to the inhibition of DNA repair. Additionally, TMZ and perifosine combination triggers caspase-dependent apoptosis and inhibits glioblastoma cell viability and proliferation. This synergy effect on glioblastoma treatment was further confirmed in vivo according to the sharp reduction in glioblastoma xenograft after the co-treatment with TMZ and perifosine. Lastly, higher BRCA1 expression is associated with a worse prognosis of recurrent glioma patients, especially the ones that received TMZ-treated. CONCLUSION Our preclinical study provides optimism for future clinical trials exploring the combination of perifosine with TMZ for glioma treatment, especially in patients with poor prognosis of glioblastoma and recurrence. In conclusion, our study suggests that the combination of TMZ and perifosine holds promise as a strategy for glioblastoma treatment.