TR-12: OKN-007: A NOVEL COMPOUND FOR TREATING PEDIATRIC GLIOBLASTOMA

Brain tumors are the most common solid tumor in children, and despite current treatment options including surgery, chemotherapy, and radiation for high-grade gliomas, survival in these patients remains very poor. This research represents promising pre-clinical data of a novel compound, OKN-007 (OKlahoma Nitrone 007, a disulfonyl derivative of α-phenyl-tert-butyl nitrone (PBN)), as a new clinical therapy for pediatric high-grade gliomas (pHGGs). The objective is to establish if pHGGs, which are often hard to surgically resect, can be treated with OKN-007, either as a single agent or in combination with currently used chemotherapeutic agents. OKN-007 may be an ideal candidate for treating pHGGs due to its multiple anti-cancer effects as seen in rat and adult gliomas, including inducing apoptosis, inhibiting cell proliferation and inhibiting angiogenesis. Morphological magnetic resonance imaging (MRI) of xenograft nude athymic mice injected with pHGG cells TCCC3752 is used in this study to assess brain tumor volumes for response to therapy. Preliminary data regarding the regression of pHGGs in mice following treatment with OKN-007 is presented. Mean survival was found to be significantly increased with OKN-007 treatment in responsive animals compared to an untreated group, p < 0.05. Immunohistochemistry and microarray will be used to assess levels of angiogenic markers (VEGF, HIF-1α, MVD), markers of cell differentiation (CAIX) and cell proliferation (Glut-1, MIB-1), apoptosis markers (cleaved caspase 3) and assess inhibition of TGFB and PDGFR complexes and downstream pathways, which are overexpressed in tumors and thought to play a role in oncogenesis and progression. OKN-007 is currently an investigational drug undergoing clinical trial evaluation for recurrent gliomas in adults but will still require FDA approval for use in pediatric patients. An outcome of the proposed research is to incorporate the pre-clinical data in an IND application in order to translate this research to the clinic and benefit children with pHGGs.