MnTE-2-PyP as a radioprotector in prostate cancer therapy

MnTE-2-PyP 作为前列腺癌治疗中的放射防护剂

基本信息

批准号：
8923175
负责人：
REBECCA E OBERLEY-DEEGAN
金额：
$ 31.94万
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：
2014
资助国家：
美国
起止时间：
2014-09-08 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8923175
关键词：
Adverse effects Affect Animals Antioxidants Atrophic Cell Proliferation Cells Cessation of life Chronic Data Development Dose EP300 gene Employee Strikes Enzymes Erectile dysfunction FDA approved Fibroblasts Fibrosis Free Radicals Gene Expression Generations Genes Genitourinary system Growth Health Human Hydrogen Peroxide In Vitro Incontinence Inflammation Inflammatory Inflammatory Response Injury Laboratories Lead Left Life Malignant neoplasm of prostate Measures Mediating Metabolic Metabolism NADPH Oxidase Neoplasm Metastasis Normal Cell Normal tissue morphology Oxidative Stress Pathway interactions Patients Pelvis Pharmaceutical Preparations Play Process Proctitis Production Prostate Cancer therapy Prostatic Neoplasms Quality of life Radiation Radiation induced damage Radiation therapy Radio Reaction Reactive Oxygen Species Relative (related person)Role Signal Transduction Superoxides Testing Therapeutic Time Tissues Treatment outcome Tumor Tissue Work Xenograft Model antitumor agent cancer cell cancer radiation therapy cell killing cytokine histone acetyltransferase in vivo inhibitor/antagonist irradiation killings men migration oxidative damage prevent prostate cancer cell radiation-induced injury response small molecule targeted treatment transcription factor tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Roughly 1.5 million US men living today have been treated with radiation therapy for prostate cancer and the number is expected to increase. The majority of these patients will suffer significant reduction in quality of life (i.e., erectile dysfunction, incontinence and proctitis) ad there are no FDA approved treatments to protect normal pelvic tissues from radiation-induced damage. Radiation exposure leads to free radical-mediated oxidative damage to normal tissues leading to fibrosis. The activation of p300 helps to drive persistent inflammation and fibrosis after irradiation. Cancer cells have increased metabolic production of reactive oxygen species (ROS) and p300 activity, relative to normal cells, which have been shown to drive cancer progression. Thus, suppressing radiation-induced ROS and p300 activity can act as both a radio-protector in normal tissues while inhibiting pro-survival and progression pathways in cancer cells. MnTE-2-PyP is a small molecule antioxidant, which scavenges a variety of ROS and reduces p300 activity. Preliminary data demonstrate that MnTE-2-PyP protects urogenital tissues from radiation-induced damage, while enhancing prostate cancer killing. The overall hypothesis of this proposal is that MnTE-2-PyP both scavenges ROS and inhibits p300 activity, which protects normal tissue injury by suppressing fibrosis while at the same time inhibiting tumor progression. Specific Aim 1 will determine whether MnTE-2-PyP protects normal pelvic tissues from radiation-induced inflammation by inhibiting both NADPH oxidase derived ROS and p300 activity. We will determine whether: 1. MnTE-2-PyP protects normal tissues from radiation damage by inhibiting ROS and p300 2. MnTE-2-PyP through ROS scavenging and p300 inhibition prevents pro-fibrotic signaling in fibroblasts exposed to irradiation 3. MnTE-2-PyP protects normal tissues by inhibiting Th2 inflammatory response by inhibiting NADPH oxidase- derived ROS and p300 activity. Specific Aim 2 will determine whether MnTE-2-PyP inhibits the progression of irradiated prostate cancer cells both in vitro and in vivo via ROS scavenging and p300 inhibition. In this aim it will be demonstrated that: 1. MnTE-2-PyP sensitizes prostate cancer cells to irradiation in vitro and in vivo 2. The manipulation of p300 and/or ROS affects the ability of MnTE-2-PyP to inhibit pro-survival and pro-angiogenic pathways necessary for tumor survival. 3. MnTE-2-PyP inhibits tumor growth and metastasis in an irradiated orthotopic xenograft model while protecting normal tissues. The completion of the studies will provide an in depth mechanistic understanding of the mechanisms by which MnTE-2-PyP inhibits normal tissue injury, while reducing prostate cancer growth during prostate cancer radiotherapy. Understanding how MnTE-2-PyP works as a radio-protector, can lead to the development more targeted therapies to enhance treatment outcomes in prostate cancer radiotherapy.

描述（由申请人提供）：当今，大约有 150 万美国男性接受了前列腺癌放射治疗，而且这一数字预计还会增加。这些患者中的大多数将遭受生活质量的显着下降（即勃起功能障碍、失禁和直肠炎），并且没有 FDA 批准的治疗方法来保护正常盆腔组织免受辐射引起的损伤。辐射暴露会导致自由基介导的对正常组织的氧化损伤，从而导致纤维化。 p300 的激活有助于驱动辐射后持续的炎症和纤维化。相对于正常细胞，癌细胞代谢产生的活性氧 (ROS) 和 p300 活性有所增加，这已被证明可以推动癌症进展。因此，抑制辐射诱导的 ROS 和 p300 活性既可以充当正常组织中的放射保护剂，又可以抑制癌细胞中的促生存和进展途径。 MnTE-2-PyP是一种小分子抗氧化剂，可清除多种ROS并降低p300活性。初步数据表明，MnTE-2-PyP 可以保护泌尿生殖组织免受辐射引起的损伤，同时增强前列腺癌的杀灭作用。该提案的总体假设是，MnTE-2-PyP 既清除 ROS，又抑制 p300 活性，从而通过抑制纤维化来保护正常组织损伤，同时抑制肿瘤进展。具体目标 1 将确定 MnTE-2-PyP 是否通过抑制 NADPH 氧化酶衍生的 ROS 和 p300 活性来保护正常盆腔组织免受辐射引起的炎症。我们将确定是否： 1. MnTE-2-PyP 通过抑制 ROS 和 p300 来保护正常组织免受辐射损伤 2. MnTE-2-PyP 通过 ROS 清除和 p300 抑制来防止暴露于辐射的成纤维细胞中的促纤维化信号传导 3. MnTE- 2-PyP 通过抑制 NADPH 氧化酶衍生的 ROS 和 p300 来抑制 Th2 炎症反应，从而保护正常组织活动。具体目标 2 将确定 MnTE-2-PyP 是否通过 ROS 清除和 p300 抑制在体外和体内抑制受辐射的前列腺癌细胞的进展。在此目标中，将证明： 1. MnTE-2-PyP 在体外和体内使前列腺癌细胞对辐射敏感 2. p300 和/或 ROS 的操作会影响前列腺癌细胞 MnTE-2-PyP 抑制肿瘤存活所需的促存活和促血管生成途径的能力。 3. MnTE-2-PyP 在受辐射的原位异种移植模型中抑制肿瘤生长和转移，同时保护正常组织。研究的完成将为 MnTE-2-PyP 抑制正常组织损伤，同时减少前列腺癌放射治疗期间前列腺癌生长的机制提供深入的了解。了解 MnTE-2-PyP 如何作为放射保护剂发挥作用，可以导致开发更有针对性的疗法，以提高前列腺癌放射治疗的治疗效果。