O2.04TREATMENT WITH OMX-4.80 A TUMOR-PENETRATING TUNABLE OXYGEN CARRIER REDUCES TUMOR HYPOXIA AND DRAMATICALLY ENHANCES RADIATION THERAPY IN INTRACRANIAL MODELS OF GLIOBLASTOMA

摘要

We have developed OMX-4.80, a tunable oxygen carrier from the H-NOX protein family, that preferentially accumulates in tumor tissue, reduces hypoxia and enhances radiotherapy (RT). Tumor hypoxia is associated with poor patient outcomes in multiple solid tumors including glioblastoma (GB) and is thought to be a major contributor to poor cancer responses to chemo and radiation therapy. Here, we show that OMX-4.80 administered i.v. into the tail vein of mice bearing orthotopic GB passes the blood-tumor barrier, penetrates deep into intracranial tumors, and significantly reduces tumor hypoxia in a dose-dependent manner. Hypoxia reduction is demonstrated by a significant decrease in levels of hypoxia inducible factor, HIF1α, and the external hypoxia marker pimonidazole as assessed by IHC and image analysis. Furthermore, hypoxia before and after treatment is compared in the individual tumors by concurrent immunostaining of tumors with a long-term hypoxia marker, Glut1, and short-lived HIF-1α. These data reveal >50% reduction in hypoxic tumor area after OMX-4.80 treatment confirming the effectiveness of OMX-4.80 in reducing hypoxia in individual tumors. When OMX-4.80 treatment was coupled with a single high dose of RT, we observed a 2.7-fold increase in tumor growth delay and 2.9-fold longer survival (p < 0.05, by logrank). Toxicology studies in rodents and dogs with single and multiple supratherapeutic doses of OMX-4.80 revealed a good safety profile affirming its suitability for clinical development. In conclusion, our results indicate that OMX-4.80 is an effective and promising RT enhancer that warrants clinical development in GB patients.