Background and Objective
RRx-001 is a radio-, immune- and chemosensitizing pan-epigenetic inhibitor with vascular normalizing properties under investigation in multiple Phase II clinical trials. Vascular normalization refers to the remodeling of the immature, crowded and dysfunctional tumor capillary network that is pruned typically through the action of anti-VEGF therapy and results in improved tumor blood flow and oxygenation. One benefit of vascular normalization is the improved penetration of cytotoxic and other therapies into the tumor leading to better responses and potentially improved survival.
MRI studies in a Phase 1/2 clinical trial of RRx-001 with radiation in brain metasteses showed alterations in tumor blood flow suggesting vascular normalization. The purpose of these experiments was to determine whether vascular normalization after administration of RRx-001 that had been previously observed both clinically and preclinically in heterotopically implanted syngeneic tumors, would increase the delivery and accumulation of systemically administered irinotecan (CPT-11) or temozolomide (TMZ) in orthotopically implanted gliomas and whether an increase in survival would be observed.
Human glioblastoma cells (GBM43), maintained as serially passaged subcutaneous xenografts in athymic mice were implanted intracranially in six-week-old athymic mice. In three separate experiments, 12 days after implantation, mice were treated with (1) RRx-001, (10 mg/kg IV); (2) TMZ, (20 mg/kg, IV or 25 mg/kg, PO) or irinotecan (0.4 mg); (3) TMZ (20 mg/kg or 25 mg/kg, PO) or irinotecan (0.4 mg) 4 hours after RRx-001 (10 mg/kg) and (4) saline control. Dosing was every 6 days in 4 cycles. Animals were euthanized as the symptoms from the increasing tumor burden prevented access to food or water. Tumor tissue was collected from a subset of animals 24 h after last dose of chemotherapy. Analysis of irinotecan content in tumor tissue was carried out by HPLC and temozolomide by LCMS.
In all three experiments, pretreatment with RRx-001 increased the concentration of irinotecan and IV and PO temozolomide in the tumor tissue. The combination groups also had statistically significant greater survival compared to the cytotoxic drug and RRx-001 alone and against control.
Vascular normalization-enhanced delivery of standard cytotoxics mediated by RRx-001 may improve the delivery of cytotoxic therapy into tumor tissue, particularly in difficult to treat brain cancers, leading to enhanced responses and improved survival and warrants further preclinical and clinical investigation.
Citation Format: Pedro Cabrales, Bryan Oronsky, Jan Scicinski. Enhanced uptake and accumulation of temozolomide and irinotecan in orthotopically-implanted gliomas by vascular priming with RRx-001. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2165.