Use of radioprotector in rectal cancer

项目摘要 大多数被诊断患有直肠癌的患者将接受放射治疗来治疗他们的肿瘤。长- 针对结肠直肠区域的放射治疗的长期并发症是肠纤维化，直肠壁损伤， 肠失禁，直肠和膀胱出血以及骨盆骨折，并且没有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引起的损伤。辐射暴露导致 自由基介导的对正常组织的氧化损伤导致纤维化。癌细胞的新陈代谢 相对于正常细胞，活性氧（ROS）的产生已被证明是癌症的驱动因素 进展因此，抑制辐射诱导的ROS将作为正常组织中的辐射保护剂 同时抑制癌细胞中的促存活和进展途径。BMX-001是一种小分子抗氧化剂， 清除活性氧初步数据表明，BMX-001保护直肠组织免受辐射- 诱导损伤，同时增强结直肠癌杀伤。这一建议的总体假设是，小轮车- 001将保护正常组织免受辐射引起的损伤，但不能保护患者体内的癌细胞 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： BMX-001如何防止辐射诱导的上皮功能障碍，以及BMX-001如何防止血液化疗， 辐射毒性将确定BMX-001是否通过以下途径预防血液学放化疗毒性： NRF 2/MnSOD信号传导和氧化应激和GI损伤的潜在生物标志物将在 辐射诱导损伤的慢性体内模型。具体目标2将确定安全性和有效性， 作为直肠癌的辐射保护剂通过II期临床试验。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 接受全新辅助放化疗，然后进行手术。具体目标3将确定潜在的 可用于证明BMX-001在人体中的辐射损伤和辐射防护功效的生物标志物 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 将评价放化疗后BMX-001或安慰剂对照患者的炎症、正常 组织损伤纤维化和氧化应激此外，将在血液中评价氧化应激标志物， 尿样研究的完成将使人们深入了解 BMX-001抑制正常组织损伤的机制以及BMX-001是否可用于直肠癌 患者作为一种有效的辐射保护剂，并可普遍适用于治疗其他癌症， 盆腔照射

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.