Abstract

Vascular normalisation refers to a ‘remodeling’ of the dysfunctional tumour capillary network, which regresses under the influence of anti-VEGF treatment, resulting in improved blood flow and oxygenation. RRx-001 is an anti-CD47-SIRPα small molecule with vascular normalising properties under investigation in clinical trials for the treatment of glioblastoma, brain metastases, lung cancer and colorectal cancer, with FDA Orphan Drug Designation in glioblastoma and other tumour types. This study investigated whether the improved oxygenation and perfusion that has been previously observed with RRx-001 both preclinically and clinically in the context of a brain metastasis trial was correlated with increased penetration and accumulation of the cytotoxic chemotherapies, irinotecan and temozolomide, in orthotopically implanted gliomas, priming tumours for improved response. The experiments demonstrate that administration of RRx-001 prior to temozolomide or irinotecan results in significantly increased uptake of irinotecan and temozolomide in orthotopic glioma tumours. Since the success of chemotherapy in the brain (and outside of it) is limited by subtherapeutic tumoral drug concentrations, vascular normalisation-enhanced delivery of standard cytotoxics as demonstrated with RRx-001 may mitigate or reverse clinical drug resistance and thereby improve the outcome of cancer therapy, particularly in the brain.

摘要

血管正常化是指功能失调的肿瘤毛细血管网络的“重塑”，在抗 VEGF 治疗的影响下会退化，从而改善血流和氧合。RRx-001是一种抗 CD47-SIRPα 小分子，具有血管正常化特性，正在临床试验中用于治疗胶质母细胞瘤、脑转移瘤、肺癌和结直肠癌，并获得 FDA 孤儿药指定用于胶质母细胞瘤和其他肿瘤类型。本研究调查了先前在脑转移试验的临床前和临床上观察到的 RRx-001 改善的氧合和灌注是否与原位植入的神经胶质瘤中细胞毒性化学疗法伊立替康和替莫唑胺的渗透和积累增加相关, 启动肿瘤以提高反应。实验表明，在替莫唑胺或伊立替康之前施用 RRx-001 可显着增加原位神经胶质瘤中伊立替康和替莫唑胺的摄取。由于大脑（及其外部）化疗的成功受到亚治疗性肿瘤药物浓度的限制，如 RRx-001 所证明的，标准细胞毒性药物的血管正常化增强递送可以减轻或逆转临床耐药性，从而改善癌症的结果治疗，尤其是在大脑中。