Abstract Recurring activating mutations, amplifications and allelic losses of the PTEN negative repressor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling pathway are major contributors to the poor survival of patients with H3K27-altered, diffuse midline gliomas (DMG), including those diagnosed in the pons as diffuse intrinsic pontine glioma (DIPG). These finding underscore the clinical potential of therapies targeting this axis. PI3K activation is further enhanced by recurring focal gains to PDGFRA, which is naturally overexpressed in oligodendrocyte precursor (OPC) cells; the cell of origin of H3K27-altered, DMG. We identified PIK3CA as genetic dependency in DMG, using a CRISPR-Cas9 deletion strategy, and therapeutically targeted PIK3CA using the brain-penetrant PI3K inhibitor paxalisib. To exploit this vulnerability, we optimized the preclinical use of paxalisib, identifying both precision medicine combination strategies and systemic interventions reducing side effects and eliciting profound tumor control. Mechanisms of adaptation and plasticity were investigated using Xenium spatial transcriptomics using in vivo PDX tumor tissues following acute and endpoint paxalisib treatment. These analyses identified that suppression of the PI3K pathway led to increased expression of PDGFRA, highlighting the potential of combining paxalisib with the brain-penetrant PDGFRA inhibitor avapritinib. Avapritinib is well-tolerated and has shown some therapeutic promise in DIPG patients harboring amplified or mutant PDGFRA. Using the RA055 PDX xenograft model (H3.3K27M, PPM1D and PDGFRA-altered), paxalisib and avapritinib were evaluated both as monotherapies and in combination. Paxalisib and avapritinib each significantly extended survival compared to control (57-days and 59-days, respectively, vs. untreated, 51-days, P 0.01). Notably, their combination resulted in a markedly enhanced survival benefit (64.5-days, P 0.0001). Through our meticulous investigations of toxicity and resistance mechanisms, we have crafted a treatment strategy designed to inhibit key oncogenic pathways, minimize side effects, and overcome resistance. Our ultimate goal is to translate these efforts into significantly improved outcomes for patients with DIPG and other brain tumors.
Duchatel et al. (Fri,) studied this question.
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