Use of radioprotector in rectal cancer

放射防护剂在直肠癌中的应用

基本信息

批准号：
10606500
负责人：
Chi Lin
金额：
$ 59.33万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-08 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606500
关键词：
Acute Address Adverse effects American Cancer Society Antioxidants Anus Apoptosis Area BMX gene Bladder Blood Cancer Patient Cell Death Induction Cell Proliferation Cells Chronic Clinical Colorectal Colorectal Cancer Combined Modality Therapy DNA Damage Data Diagnosis Disease-Free Survival Epithelium FDA approved Fecal Incontinence Fibrosis Fluorouracil Free Radicals Functional disorder Genitourinary system Growth Hematology Hemorrhage Histologic Human Inflammation Injury Insurance Intestinal permeability Intestines Malignant Neoplasms Malignant neoplasm of anus Manganese Mediating Metabolic Mucous Membrane Neoadjuvant Therapy Normal Cell Normal tissue morphology Operative Surgical Procedures Oxidative Stress Paraffin Embedding Pathway interactions Patient-Focused Outcomes Patients Pelvis Permeability Pharmaceutical Preparations Phase II Clinical Trials Placebo Control Porphyrins Postoperative Complications Production Quality of life Radiation Radiation Dose Unit Radiation Monitoring Radiation Protection Radiation Toxicity Radiation exposure Radiation induced damage Radiation therapy Randomized Reactive Inhibition Reactive Oxygen Species Rectal Cancer Rectum Resected SOD2 gene Safety Sampling Signal Transduction Skin Specimen Stains Structure Superoxides Survival Rate Therapeutic Tight Junctions Tissues Toxic effect Transforming Growth Factor beta Translating Urine Work acute toxicity biomarker identification cancer cell cancer radiation therapy chemoradiation chemotherapy cytotoxic efficacy evaluation gastrointestinal improved in vivo Model inflammatory marker insight irradiation oxidative damage pelvis fracture phase II trial potential biomarker prevent primary endpoint radiation-induced tissue damage rectal secondary endpoint senescence side effect small molecule stem cell biomarkers stem cells tissue injury tumor tumor growth tumor progression

项目摘要

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.

项目概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肿瘤。长的- 针对结直肠区域的放射治疗的长期并发症包括肠纤维化、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 批准的治疗方法保护正常直肠和肛门组织免受辐射损伤。辐射暴露会导致游离自由基介导的对正常组织的氧化损伤导致纤维化。癌细胞的新陈代谢增加相对于正常细胞，活性氧 (ROS) 的产生已被证明会导致癌症进展。因此，抑制辐射诱导的 ROS 将充当正常组织中的辐射保护剂同时抑制癌细胞的促生存和进展途径。 BMX-001是一种小分子抗氧化剂，清除ROS。初步数据表明 BMX-001 可以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。该提案的总体假设是 BMX- 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： BMX-001 可以防止辐射引起的上皮功能障碍，以及 BMX-001 如何预防血液化疗辐射毒性。将确定 BMX-001 是否通过以下方式预防血液放化疗毒性： NRF2/MnSOD 信号传导以及氧化应激和胃肠道损伤的潜在生物标志物将在辐射引起的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放射防护剂，已通过 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放射防护剂接受全面新辅助放化疗治疗，然后进行手术。具体目标 3 将确定潜力可用于证明 BMX-001 对人体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放化疗后将评估炎症、正常情况组织损伤、纤维化和氧化应激。此外，还将评估血液中的氧化应激标记物和尿液样本。研究的完成将提供对这一现象的深入的机制理解。 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有效的放射防护者，可以普遍适用于治疗其他癌症盆腔照射。