EPEN-12. Sunitinib induces apoptosis-mediated cytotoxicity in PFA ependymoma

Abstract

Abstract Ependymoma (EPN) has been previously shown to be selectively targeted by three classes of FDA-approved chemotherapy drugs: fluorinated pyrimidines, retinoids, and a subset of small molecule receptor tyrosine kinase inhibitors (RTKIs). We have identified sunitinib malate as an RTKI with ependymoma selectivity, in addition to previously identified ependymoma-selective RTKIs axitinib, imatinib, and pazopanib. Sunitinib—which targets VEGFR, PDGFR and c-kit—elicited unexpectedly high levels of cytotoxic apoptosis (caspase 3/7 cleavage) in EPN PFA cell lines harboring high-risk chromosome 1q gain and 6q loss. In this in-vitro screen of 100+ FDA-approved chemotherapy drugs, sunitinib was the only RTKI in the top five most cytotoxic drugs, a group that included idarubicin HCl, topotecan HCl, daunorubicin HCl, and doxorubicin. Additionally, sunitinib exhibited comparable caspase 3/7 cleavage levels in normoxia and hypoxia, suggesting that this therapy would be as effective in treatment of tumors with potentially resistant hypoxic necrotic cores. The effect of sunitinib on EPN cellular proliferation was tracked visually using Incucyte cell imaging technology, demonstrating consistent dose-dependent inhibition of proliferation. Sunitinib achieved more acute upregulation of apoptosis than axitinib, an EPN-selective RTKI currently being studied in preclinical models. A prior phase II trial of sunitinib in pediatric EPN and high-grade glioma showed that treatment was well tolerated but with no clinical benefit as a monotherapy. However, given encouraging clinical results of combining sunitinib with radiation, our ongoing preclinical studies of sunitinib in EPN are being conducted in the context of radiation which is standard treatment for EPN. Sunitinib presents a promising treatment to an intractable pediatric brain tumor that exhibits high rates of relapse and morbidity in affected individuals.