ID #1041 Evaluation of the antitumor effect of paxalisib in combination with oncolytic virotherapy for Diffuse Midline Glioma

Diffuse Midline Gliomas (DMGs) are aggressive brain tumors with dismal prognosis and lack of viable treatments. Thus, there is an urgent need to develop innovative therapies. Oncolytic adenovirus Delta-24-RGD has demonstrated provided clinical safety in ongoing trials, but its single-agent efficacy remains limited. Paxalisib, a dual PI3K/mTOR inhibitor developed by Kazia Therapeutics, crosses the blood-brain barrier and shows clinical tolerability in DMG dose-escalation studies. The PI3K/mTOR pathway is aberrantly activated in most pediatric brain tumors, promoting tumor cell survival and immune suppression, making it an ideal target for combination with oncolytic virotherapy. We evaluated Delta-24-RGD in combination with paxalisib using in vitro assays and orthotopic DMG models (SU-DIPG-XIIIp*; H3K27M). Paxalisib was dosed at 5 mg/kg/day, three times weekly for one month, following intratumoral virus delivery. Primary endpoints were median overall survival (OS) and long-term survivor rate; safety was assessed by complete blood count. Our results demonstrated that Delta-24-RGD combined with paxalisib resulted in synergistic reductions in cell viability and enhanced viral replication. Ultimately in vivo, the combination significantly extended median OS compared to vehicle and paxalisib monotherapy. Notably, 33% of combination-treated animals achieved long-term survival (>120 days), versus 25% for Delta-24-RGD alone and 10% for paxalisib monotherapy. No treatment-related toxicity was observed. These results demonstrate that combining paxalisib with oncolytic adenoviruses synergistically enhances anti-tumor efficacy in preclinical DMG models, achieving clinically meaningful long-term survival rates with favorable tolerability. The mechanistic basis involves both direct PI3K/mTOR inhibition and enhanced anti-tumor immunity. These findings support clinical translation of this combination approach for DMG and other pediatric CNS malignancies with PI3K/mTOR pathway activation.