Synergistic targeting of PDGFRA/KIT and metabolic pathways in pediatric high-grade glioma: Translational evaluation of avapritinib combined with atorvastatin
Pediatric high-grade gliomas (pHGGs) are highly aggressive, incurable brain tumors that primarily affect children. Our research group previously identified an important growth factor receptor, PDGFRA, which is overactive and causes uncontrolled growth of pHGG cancer cells. We developed a new treatment approach for patients diagnosed pHGG with PDGFRA gene alterations using the small-molecule PDGFRA inhibitor avapritinib. This drug effectively targeted patient-derived pHGG cell lines and pHGG mouse models. Furthermore, we reported the first clinical experience with this drug in eight patients with pHGG, demonstrating that it was safe and well tolerated. Although some patients initially responded well to avapritinib, their tumors eventually stopped responding and grew back. In our ongoing work, we aim to understand how pHGG cells manage to escape treatment and grow back after avapritinib therapy. We found that the cells undergo metabolic changes after both short-term and long-term avapritinib treatment, altering how they generate energy to support their uncontrolled growth. These findings suggest that pHGG cells may reprogram their metabolism as a way to resist the effects of avapritinib. We hypothesized that targeting these metabolic survival mechanisms might enhance the effectiveness of avapritinib. Indeed, we found that the metabolic inhibitor atorvastatin increases the toxic effect of avapritinib when both drugs are combined.
Project Goals
We previously identified metabolic shifts in pHGG cells treated with the PDGFRA inhibitor avapritinib and demonstrated that targeting these elevated metabolic pathways using the metabolic inhibitor atorvastatin, in combination with avapritinib, results in increased cell death of pHGG cell lines. In this study, we will assess the therapeutic benefit and molecular effects of this combinatorial treatment in patient-derived pHGG mouse models. Specifically, we will evaluate the pre-clinical safety and efficacy of this treatment in three mouse models with distinct molecular characteristics (efficacy study cohort). In addition, we will perform detailed molecular analyses of mouse tumor tissues of a independent mouse cohort (mechanistic study cohort). The endpoint of this study will be the initiation of a clinical trial to evaluate the safety and efficacy of avapritinib and atorvastatin combination treatment for patients newly diagnosed with PDGFRA-altered pHGG. By combining avapritinib with therapies targeting the upregulated metabolic pathways, we aim to enhance its therapeutic efficacy. Our ultimate goal is to establish a novel combinatorial treatment approach as a new therapy for a patient population in great need. If successful, this approach could not only benefit children with pHGG but also help overcome treatment resistance in other cancers, thereby enhancing the clinical impact of existing therapies and providing new hope for patients facing these challenging diseases.
