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

描述(由申请人提供)： 今天，大约有150万美国男性接受了前列腺癌的放射治疗，预计这一数字还会增加。这些患者中的大多数将遭受生活质量的显著下降(即勃起功能障碍、大小便失禁和直肠炎)，而且FDA没有批准的治疗方法来保护正常的盆腔组织免受辐射损伤。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。P300的激活有助于推动辐射后的持续性炎症和纤维化。相对于正常细胞，癌细胞增加了活性氧簇(ROS)和p300活性的代谢产物，这已被证明是推动癌症进展的因素。因此，抑制辐射诱导的ROS和p300活性可以在正常组织中起到辐射保护剂的作用，同时抑制癌细胞的促生存和进展途径。MnTE-2-PYP是一种小分子抗氧化剂，能清除多种ROS，降低p300活性。初步数据显示，MnTE-2-PYP保护泌尿生殖系统组织免受辐射损伤，同时增强前列腺癌的杀伤力。这一提议的总体假设是，MnTE-2-PYP既清除ROS又抑制p300活性，通过抑制纤维化同时抑制肿瘤进展来保护正常组织损伤。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诱导的炎症。我们将确定：1.MnTE-2-PYP是否通过抑制ROS和p300来保护正常组织免受辐射损伤。2.MnTE-2-PYP通过清除ROS和抑制P300来阻止辐射暴露的成纤维细胞的促纤维化信号。3.MnTE-2-PYP通过抑制NADPH氧化酶衍生的ROS和p300活性来抑制Th2炎症反应，从而保护正常组织。特异性目标2将确定MnTE-2-PYP是否通过清除ROS和抑制p300而在体外和体内抑制受照射的前列腺癌细胞的进展。为此，将证明：1.MnTE-2-PYP在体内外对前列腺癌细胞的辐射增敏作用2.操纵p300和/或ROS影响前列腺癌细胞对辐射的敏感性 MnTE-2-PYP抑制肿瘤存活所必需的促生存和促血管生成途径的能力。3.在保护正常组织的同时，MnTe-2-PYP可抑制受照射的异种移植瘤模型中肿瘤的生长和转移。这些研究的完成将提供对MnTE-2-PYP在前列腺癌放射治疗过程中抑制正常组织损伤同时减少前列腺癌生长的机制的深入机制的理解。了解MnTE-2-PYP作为放射防护剂的作用，可以导致开发更有针对性的治疗方法，以提高前列腺癌放射治疗的治疗结果。

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.