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:8760810
- 负责人:
- 金额:$ 33.01万
- 依托单位:
- 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:
- 关键词:Adverse effectsAffectAnimalsAntioxidantsAtrophicCell ProliferationCellsCessation of lifeChronicDataDevelopmentDoseEP300 geneEmployee StrikesEnzymesErectile dysfunctionFDA approvedFibroblastsFibrosisFree RadicalsGene ExpressionGenerationsGenesGenitourinary systemGrowthHumanHydrogen PeroxideIn VitroIncontinenceInflammationInflammatoryInflammatory ResponseInjuryLaboratoriesLeadLeftLifeMalignant neoplasm of prostateMeasuresMediatingMetabolicMetabolismNADPH OxidaseNeoplasm MetastasisNormal CellNormal tissue morphologyOxidative StressPathway interactionsPatientsPelvisPharmaceutical PreparationsPlayProcessProctitisProductionProstate Cancer therapyProstatic NeoplasmsQuality of lifeRadiationRadiation induced damageRadiation therapyRadioReactionReactive Oxygen SpeciesRelative (related person)RoleSignal TransductionSuperoxidesTestingTherapeuticTimeTissuesTreatment outcomeTumor TissueWorkXenograft Modelantitumor agentcancer cellcancer radiation therapycell killingcytokinehistone acetyltransferasein vivoinhibitor/antagonistirradiationkillingsmenmigrationoxidative damagepreventprostate cancer cellpublic health relevanceresponsesmall moleculetranscription factortumortumor growthtumor 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):
目前,大约有150万美国男性接受过前列腺癌放射治疗,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降低(即,勃起功能障碍、失禁和直肠炎),并且没有FDA批准的治疗来保护正常骨盆组织免受辐射诱导的损伤。辐射暴露导致对正常组织的自由基介导的氧化损伤,从而导致纤维化。p300的激活有助于驱动照射后的持续炎症和纤维化。相对于正常细胞,癌细胞增加了活性氧(ROS)和p300活性的代谢产物,这已被证明会推动癌症进展。因此,抑制辐射诱导的ROS和p300活性可以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。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保护泌尿生殖系统组织免受辐射诱导的损伤,同时增强前列腺癌的杀伤作用。该提议的总体假设是MnTE-2-PyP既清除ROS又抑制p300活性,这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。我们将确定是否:1。MnTE-2-PyP通过抑制ROS和p300保护正常组织免受辐射损伤。MnTE-2-PyP通过ROS清除和p300抑制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活性来抑制Th 2炎症反应,从而保护正常组织。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照射的前列腺癌细胞的进展。在这个目标中,它将被证明:1。MnTE-2-PyP在体外和体内对前列腺癌细胞辐射增敏2.对p300和/或ROS的操纵影响了细胞的增殖。
MnTE-2-PyP抑制肿瘤存活所必需的促存活和促血管生成途径的能力。3. MnTE-2-PyP在辐射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。这些研究的完成将提供对MnTE-2-PyP抑制正常组织损伤的机制的深入机制理解,同时减少前列腺癌放疗期间的前列腺癌生长。了解MnTE-2-PyP如何作为放射保护剂,可以导致开发更具靶向的治疗方法,以提高前列腺癌放疗的治疗效果。
项目成果
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{{ truncateString('REBECCA E OBERLEY-DEEGAN', 18)}}的其他基金
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
- 批准号:
8923175 - 财政年份:2014
- 资助金额:
$ 33.01万 - 项目类别:
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