Use of radioprotector in rectal cancer

项目总结 大多数被诊断为直肠癌的患者将接受放射治疗来治疗他们的肿瘤。长- 直肠放射治疗的长期并发症是肠纤维化，直肠壁损伤， 大便失禁、直肠和膀胱出血以及骨盆骨折，目前还没有FDA批准的治疗方法 以保护正常的直肠和肛门组织免受辐射损伤。辐射暴露导致免费 自由基介导的对正常组织的氧化损伤导致纤维化。癌细胞新陈代谢增加 相对于正常细胞产生的活性氧物种(ROS)，已被证明是导致癌症的原因 进步。因此，抑制辐射诱导的ROS在正常组织中既起到辐射防护剂的作用 同时抑制癌细胞中促进生存和进展的途径。BMX-001是一种小分子抗氧化剂， 它会捕食ROS。初步数据显示，BMX-001可保护直肠组织免受辐射。 诱导损伤，同时增强结直肠癌的杀伤力。这项提议的总体假设是小轮车- 001将保护正常组织免受辐射损伤，但不保护患者的癌细胞。 接受直肠癌和肛门癌的放射治疗。具体目标1将通过以下方式确定机制(S 哪种BMX-001可以预防辐射诱导的上皮功能障碍，以及BMX-001是如何防止血液化疗的。 辐射毒性。将确定BMX-001是否通过以下途径预防血液系统的放化疗毒性 NRF2/MnSOD信号和潜在的氧化应激和胃肠道损伤的生物标志物将在 慢性体内辐射损伤模型。具体目标2将确定 患者通过II期临床试验作为直肠癌的辐射防护剂。一项随机II期临床试验 将确定BMX-001是否是直肠癌患者正常组织的有效辐射保护剂 先接受全新辅助放化疗，然后再手术。具体目标3将确定潜力 BMX-001对人体的辐射损伤和辐射防护效果的生物标志物 从II期试验中获得的临床标本。手术切除的肿瘤和邻近的正常直肠组织 来自BMX-001或安慰剂对照的患者在化疗后将接受炎症评估，正常 组织损伤、纤维化和氧化应激。此外，还将评估血液和血液中的氧化应激标志物 尿样。研究的完成将使我们从机制上更深入地了解 BMX-001抑制正常组织损伤的机制及其是否可用于直肠癌 患者是一种有效的辐射防护剂，可以普遍适用于其他癌症的治疗 骨盆照射。

PROJECT SUMMARY The majority of patients diagnosed with rectal cancer will receive radiation therapy to treat their tumors. Long- term complications from radiation therapy directed to the colorectal region are bowel fibrosis, rectal wall damage, bowel incontinence, rectal and bladder bleeding and pelvic fracture and there are no FDA approved treatments to protect normal rectal and anal tissues from radiation-induced damage. Radiation exposure leads to free radical-mediated oxidative damage to normal tissues leading to fibrosis. Cancer cells have increased metabolic production of reactive oxygen species (ROS), relative to normal cells, which have been shown to drive cancer progression. Thus, suppressing radiation-induced ROS would act as both a radioprotector in normal tissues while inhibiting pro-survival and progression pathways in cancer cells. BMX-001 is a small molecule antioxidant, which scavenges ROS. Preliminary data demonstrate that BMX-001 protects rectal tissues from radiation- induced damage, while enhancing colorectal cancer killing. The overall hypothesis of this proposal is that BMX- 001 will protect normal tissues from radiation-induced damage, while not protecting the cancer cells in patients undergoing radiation therapy of rectal and anal cancers. Specific Aim 1 will determine the mechanism(s) by which BMX-001 protects from radiation-induced epithelial dysfunction and how BMX-001 prevents blood chemo- radiation toxicity. It will be determined whether BMX-001 prevents hematological chemoradiation toxicity through the NRF2/MnSOD signaling and potential biomarkers of oxidative stress and GI damage will be identified in a chronic in vivo model of radiation-induced damage. Specific Aim 2 will determine the safety and efficacy in patients through Phase II clinical trials as a radioprotector of rectal cancers. A randomized phase II clinical trial will determine whether BMX-001 is an efficacious radioprotector of normal tissues in rectal cancer patients undergoing total neoadjuvant chemoradiation therapy followed by surgery. Specific Aim 3 will identify potential biomarkers that can be used to demonstrate radiation damage and radioprotector efficacy of BMX-001 in human clinical specimens obtained from the Phase II trial. Surgically resected tumor and adjacent normal rectal tissues from BMX-001 or placebo controlled patients after chemoradiation will be evaluated for inflammation, normal tissue damage, fibrosis and oxidative stress. In addition, oxidative stress markers will be evaluated in blood and urine samples. The completion of the studies will provide an in depth mechanistic understanding of the mechanisms by which BMX-001 inhibits normal tissue injury and whether BMX-001 can be used in rectal cancer patients as an effective radioprotector and could be universally adapted for treatment of other cancers receiving pelvic irradiation.