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：
7150095
负责人：
CHARLES Joseph GOMER
金额：
$ 33.33万
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/7150095
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 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 Outcome 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 United States Food and Drug Administration Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Verteporfin Xenograft Model ZD-6474 aspartyl chlorin cell type chlorin e6 cyclooxygenase 1 cyclooxygenase 2 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 transcription factor tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：光动力疗法（PDT）仍然是治疗实体瘤的有效临床程序，但尚未优化该过程，并且可能会发生复发。我们建议的长期目标是提高PDT的功效。该应用程序的基本原理建立在PDT的观察结果上，该观察结果在肿瘤微环境中引起显着变化，从而导致血管生成和/或生存表型。我们发现，PDT可以在处理的肿瘤中诱导血管内皮生长因子（VEGF）的表达。 PDT后，其他血管生成因子（包括基质金属蛋白酶-9（MMP-9）以及存活分子AKT和Survivin）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将显着提高PDT的长期治疗反应性。我们进一步假设PDT介导的肿瘤微环境中的变化与MMP-9的表达和激活相关，而Survivin可以降低PDT效力。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。靶向VEGF（Avastin），VEGF受体-2（DC 101）和VEGF的受体酪氨酸激酶（ZD6474）的抗血管生成剂将在旨在检查旨在检查肿瘤和正常组织反应的实验中评估。在特定目标2中，我们将确定PDT诱导的对与MMP-9表达相关的肿瘤微环境的改变和激活对调节治疗反应性的影响。 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中属文的表达和激活对PDT反应性的影响。经过遗传修饰以表达野生型的肿瘤或Survivin的显性阴性突变形式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 [17-（Allylamlamino）-17-甲氧西乙酰甲霉素）相结合的有效性。这些目标的成功完成将提供有关PDT调制肿瘤微环境的机械信息，以及为包括PDT的靶向抑制剂（包括针对目标抑制剂）所需的转化数据。