Photodynamic Therapy Affects on the Tumor Microenvironment

光动力疗法对肿瘤微环境的影响

基本信息

批准号：
7753180
负责人：
CHARLES Joseph GOMER
金额：
$ 34.8万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-03-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753180
关键词：
17-(Allylamino)-17-demethoxygeldanamycin Abbreviations Address Affect Aminolevulinic Acid Angiogenesis Inhibitors Angiogenic Factor Apoptosis Apoptosis Inhibitor Avastin Binding Binding Proteins Borderline Personality Disorder Breast Carcinoma Bronchopulmonary Dysplasia Cell Line Cells Client Clinical DC101 Monoclonal Antibody Data Dinoprostone Dipeptides Dominant-Negative Mutation EDN2 gene Effectiveness FDA approved Fibroblast Growth Factor 2 Gelatinase B Heat shock proteins Human Human Mammary Carcinoma Hypoxia Interstitial Collagenase Knockout Mice Lead MCF7 cell MEKs Malignant Epithelial Cell Matrix Metalloproteinases Mediating Methane Mitogen-Activated Protein Kinase Kinases Modality Mono-S Mus NF-kappa B NS-398 Normal tissue morphology Pericytes Phenotype Photochemotherapy Photosensitizing Agents Phototoxicity Porfimer Sodium Procedures Prostaglandin-Endoperoxide Synthase Protein Tyrosine Kinase Proteins Proto-Oncogene Proteins c-akt Purlytin Radiation Receptor Protein-Tyrosine Kinases Recurrence Research Personnel Response Elements Role SCID Mice Serum Signal Pathway Signal Transduction Solid Neoplasm Staging Sulfonamides Therapeutic Tin Ethyl Etiopurpurin Tissue Inhibitor of Metalloproteinase-1 Tissues Treatment Efficacy Treatment Protocols Tumor Necrosis Factor-alpha Tumor Tissue Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Verteporfin Xenograft Model ZD-6474 aspartyl chlorin cell type chlorin e6 design endothelial monocyte-activating polypeptide II fetal fibrosarcoma improved in vivo inhibitor-of-apoptosis protein inhibitor/antagonist malignant breast neoplasm monoaspartyl chlorin e6 mutant nanometer programs proteinase In research study response survivin therapeutic effectiveness therapy outcome transcription factor tumor tumor xenograft

项目摘要

Photodynamic therapy (PDT) continues to be an effective clinical procedure for treating solid tumors but the procedure has not been optimized and recurrences can occur. The long-term objective of our proposal is to improve upon the efficacy of PDT. The rationale for this application builds upon observations that PDT induces significant changes within the tumor microenvironment that can lead to an angiogenic and/or survival phenotype. We have found that PDT can induce expression of vascular endothelial growth factor (VEGF) within treated tumors. Additional angiogenic factors, including matrix metalloproteinase-9 (MMP-9) as well as survival molecules, Akt and survivin, are increased and/or activated following PDT. We hypothesize that combining PDT with appropriately targeted and delivered angiogenic inhibitors will significantly improve the long-term therapeutic responsiveness of PDT. We further hypothesize that PDT mediated changes within the tumor microenvironment associated with the expression and activation of MMP- 9 and survivin can decrease PDT efficacy. Three specific aims will address our hypotheses. In specific aim 1 we will determine how best to combine antiangiogenic therapy to optimize PDT efficacy. Antiangiogenic agents that target VEGF (Avastin), VEGF receptor-2 (DC 101),and the receptor tyrosine kinase of VEGF (ZD6474) will be evaluated in experiments designed to examine tumor and normal tissue response. In specific aim 2, we will determine the impact that PDT induced alterations to the tumor microenvironment associated with MMP-9 expression and activation have on modulating treatment responsiveness. MMP-9 knockout mice will be used to determine the role of this proteinase in PDT outcomes. In specific aim 3, we will determine the impact of survivin expression and activation within the tumor microenvironment on PDT responsiveness. Tumors genetically modified to express wild type or a dominant negative mutant form of survivin will be used to determine the role of this inhibitor of apoptosis in modulating PDT tumor response. We will also determine the effectiveness of combining PDT with the Hsp90/survivin inhibitor 17-AAG[17- (allylamino)-17-demethoxygeldanamycin). The successful completion of these aims will provide mechanistic information regarding PDT modulation of the tumor microenvironment and translational data needed to justify including targeted inhibitors with PDT.

光动力疗法（PDT）仍然是治疗实体瘤的有效临床程序过程尚未优化，并且可能发生复发。我们建议的长期目标是提高PDT的功效。此应用程序的基本原理是基于PDT的观察在肿瘤微环境中引起重大变化，这可能导致血管生成和/或生存表型。我们发现PDT可以诱导血管内皮生长因子的表达（VEGF）在治疗的肿瘤中。其他血管生成因子，包括基质金属蛋白酶-9（MMP-9） PDT之后，以及生存分子（AKT和Survivin）也会增加和/或激活。我们假设将PDT与适当靶向和递送的血管生成抑制剂相结合显着提高了PDT的长期治疗反应。我们进一步假设PDT 与MMP-的表达和激活相关的肿瘤微环境中的介导的变化 9和Survivin可以降低PDT功效。三个具体目标将解决我们的假设。在特定目标1中我们将确定如何最好地结合抗血管生成疗法以优化PDT疗效。抗血管生成靶向VEGF（Avastin），VEGF受体2（DC 101）和VEGF受体酪氨酸激酶的药物（ZD6474）将在旨在检查肿瘤和正常组织反应的实验中评估。在具体目标2，我们将确定PDT引起对肿瘤微环境的改变的影响与MMP-9的表达和激活相关的是调节治疗反应能力。 MMP-9 敲除小鼠将用于确定该蛋白酶在PDT结果中的作用。在特定的目标3中，我们将确定肿瘤微环境内源性表达和激活对PDT的影响响应能力。肿瘤在遗传上修饰以表达野生型或主要的负突变体形式 Survivin将用于确定这种凋亡抑制剂在调节PDT肿瘤反应中的作用。我们还将确定将PDT与Hsp90/survivin抑制剂17-AAG相结合的有效性[17-- （Allylamino）-17-半甲氧基甘霉素）。这些目标的成功完成将提供有关PDT调制肿瘤微环境和翻译数据的机械信息需要证明具有PDT的有针对性抑制剂的合理性。