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.

项目摘要大多数被诊断为直肠癌的患者将接受放射治疗以治疗其肿瘤。长的- 肠道纤维化，直肠壁损伤，直肠区域的辐射疗法的术语并发症，肠尿失禁，直肠和膀胱出血和骨盆骨折，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诱导的损伤。辐射暴露导致自由对正常组织的自由基介导的氧化损伤导致纤维化。癌细胞的代谢增加相对于正常细胞的活性氧（ROS）的产生，这些细胞已被证明驱动癌症进展。因此，抑制辐射诱导的ROS将在正常组织中充当辐射保护剂同时抑制癌细胞中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保护直肠组织免受辐射 - 诱发损害，同时增强结直肠癌的杀戮。该提议的总体假设是BMX- 001将保护正常组织免受辐射诱导的损伤，同时不保护患者的癌细胞接受直肠和肛门癌的放射疗法。特定目标1将通过 BMX-001可保护辐射诱导的上皮功能障碍以及BMX-001如何防止血液化学化学辐射毒性。将确定BMX-001是否通过通过 NRF2/MNSOD信号传导和氧化应激和GI损伤的潜在生物标志物将在A中鉴定辐射诱导损伤的慢性体内模型。特定的目标2将决定通过II期临床试验作为直肠癌的辐射保护剂的患者。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接受全新的新辅助化学放射治疗，然后进行手术。特定目标3将确定潜力可用于证明BMX-001在人类中的辐射损伤和辐射保护剂功效的生物标志物从II期试验获得的临床标本。手术切除的肿瘤和邻近正常直肠组织从BMX-001或化学放疗后的安慰剂受控患者中，将评估炎症，正常组织损伤，纤维化和氧化应激。此外，将在血液和尿液样品。研究的完成将提供深入的机械理解 BMX-001抑制正常组织损伤以及BMX-001是否可以用于直肠癌的机制患者作为有效的放射保护剂，可以普遍适用于接受其他癌症的治疗骨盆照射。