Inhibition of PDGFR May Be a Viable Treatment Option for Meningiomas

Background: Meningiomas are the most common primary tumor in the central nervous system. Aside from surgery, no consensus on the benefit of adjuvant therapy exists for these tumors. One possible avenue to address the need for additional therapies for meningiomas is high-throughput drug screening. Through our screening efforts, we identified platelet-derived growth factor receptor (PDGFR) inhibitors as potential treatments for patients with meningiomas.

Methods: We utilized our high-throughput drug screening system, developed for central nervous system (CNS) tumors, to screen meningiomas shortly after resection. We also included previously established meningiomas cell lines in our screening efforts. We screened an expanded version of the National Cancer Institute’s Anti-Cancer Library at a 1-µm dose, in triplicate, for each tumor. After 72 hours of treatment, we evaluated tumor viability by MTS assay. Any compound that significantly reduced viability compared with an untreated control was considered a positive hit for further validation.

Results: Thus far, 12 meningiomas have been tested with our expanded screen. Ponatinib was identified as the most effective tyrosine kinase inhibitor in this cohort of compounds. Ponatinib can inhibit the Abelson murine leukemia viral oncogene homolog 1 (ABL), PDGFRa, vascular endothelial growth receptor (VEGFR), and fibroblast growth factor receptor (FGFR). Comparing the targets of Ponatinib to targets of compounds that did not significantly reduce meningioma cell viability, we were able to identify PDGFR as the receptor responsible for Ponatinib’s activity. Using dose curves, we calculate the IC50 of Ponatinib in a cell-based assay to be between 900 nm and 1 µm. To fully elucidate the efficacy of targeting the PDGFR family of tyrosine kinase inhibitors, we are in the process of screening PDGFRb inhibitors, as well as pan-PDFGR inhibitors in meningiomas. While meningiomas are not known to have activating PDGFR mutations, activation of PDGFR signaling has been shown to drive NF2 deleted arachnoid cap cells into meningiomas, making PDGFR a potential target for meningioma therapy.

Conclusion: Additional therapies are needed for the treatment of meningiomas. Using our novel cell culturing technique and high-throughput drug screening capabilities, we identified Ponatinib as a compound that significantly reduced meningioma cell viability. Additional work is needed to fully investigate the potential of targeting PDGFR signaling in meningiomas as well as in vivo experiments to validate our findings.