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方法，但程序尚未优化，可能会重复发生。我们建议的长期目标是提高PDT的疗效。该应用程序的基本原理建立在 PDT 的观察基础上诱导肿瘤微环境发生显着变化，从而导致血管生成和/或生存表型。我们发现PDT可以诱导血管内皮生长因子的表达 (VEGF) 在治疗的肿瘤内。其他血管生成因子，包括基质金属蛋白酶-9 (MMP-9) PDT 后，存活分子 Akt 和存活蛋白也会增加和/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 介导的肿瘤微环境变化与 MMP-的表达和激活相关 9和survivin会降低PDT疗效。三个具体目标将解决我们的假设。具体目标1 我们将确定如何最好地结合抗血管生成疗法来优化 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进行评估。在具体目标2，我们将确定PDT引起的肿瘤微环境改变的影响与 MMP-9 表达和激活相关的药物可调节治疗反应。基质金属蛋白酶-9 基因敲除小鼠将用于确定这种蛋白酶在 PDT 结果中的作用。在具体目标 3 中，我们将确定肿瘤微环境中生存素表达和激活对 PDT 的影响反应能力。经过基因改造以表达野生型或显性失活突变体形式的肿瘤 survivin 将用于确定这种细胞凋亡抑制剂在调节 PDT 肿瘤反应中的作用。我们还将确定 PDT 与 Hsp90/生存素抑制剂 17-AAG 相结合的有效性[17- (烯丙氨基)-17-去甲氧基格尔德霉素)。这些目标的成功实现将提供有关肿瘤微环境 PDT 调节的机制信息和转化数据需要证明 PDT 中包含靶向抑制剂的合理性。