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:7919055
- 负责人:
- 金额:$ 18.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:17-(Allylamino)-17-demethoxygeldanamycinAbbreviationsAddressAffectAminolevulinic AcidAngiogenesis InhibitorsAngiogenic FactorApoptosisApoptosis InhibitorAvastinBindingBinding ProteinsBorderline Personality DisorderBreast CarcinomaBronchopulmonary DysplasiaCell LineCellsClientClinicalDC101 Monoclonal AntibodyDataDinoprostoneDipeptidesDominant-Negative MutationEDN2 geneEffectivenessFDA approvedFibroblast Growth Factor 2Gelatinase BHeat shock proteinsHumanHuman Mammary CarcinomaHypoxiaInterstitial CollagenaseKnockout MiceLeadMCF7 cellMEKsMalignant Epithelial CellMatrix MetalloproteinasesMediatingMethaneMitogen-Activated Protein Kinase KinasesModalityMono-SMusNF-kappa BNS-398Normal tissue morphologyPericytesPhenotypePhotochemotherapyPhotosensitizing AgentsPhototoxicityPorfimer SodiumProceduresProstaglandin-Endoperoxide SynthaseProtein Tyrosine KinaseProteinsProto-Oncogene Proteins c-aktPurlytinRadiationReceptor Protein-Tyrosine KinasesRecurrenceResearch PersonnelResponse ElementsRoleSCID MiceSerumSignal PathwaySignal TransductionSolid NeoplasmStagingSulfonamidesTherapeuticTin Ethyl EtiopurpurinTissue Inhibitor of Metalloproteinase-1TissuesTreatment EfficacyTreatment ProtocolsTumor Necrosis Factor-alphaTumor TissueVascular Endothelial Growth Factor Receptor-2Vascular Endothelial Growth FactorsVerteporfinXenograft ModelZD-6474aspartyl chlorincell typechlorin e6designendothelial monocyte-activating polypeptide IIfetalfibrosarcomaimprovedin vivoinhibitor-of-apoptosis proteininhibitor/antagonistmalignant breast neoplasmmonoaspartyl chlorin e6mutantnanometerprogramsproteinase Inresearch studyresponsesurvivintherapeutic effectivenesstherapy outcometranscription factortumortumor 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一种有效的临床方法,但
过程尚未优化,可能会发生重复。我们建议的长期目标是
提高光动力疗法的疗效。这个应用程序的基本原理建立在观察到的PDT
在肿瘤微环境中引起显著变化,可导致血管生成和/或
生存表型。我们发现光动力疗法可以诱导血管内皮生长因子的表达。
(血管内皮生长因子)在治疗肿瘤内。其他血管生成因子,包括基质金属蛋白酶-9(MMP9)
以及生存分子Akt和Survivin,在PDT后增加和/或激活。我们
假设将PDT与适当靶向和给药的血管生成抑制剂相结合将
显著提高PDT的远期疗效。我们进一步假设光动力疗法
肿瘤微环境中与基质金属蛋白酶表达和激活相关的变化
9和Survivin可降低PDT疗效。三个具体目标将解决我们的假设。在特定目标中1
我们将确定如何最好地结合抗血管生成治疗来优化PDT的疗效。抗血管生成
针对血管内皮生长因子(阿瓦斯丁)、血管内皮生长因子受体-2(DC 101)和血管内皮生长因子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……里面
具体目标2,我们将确定光动力疗法对肿瘤微环境的影响
与基质金属蛋白酶-9的表达和激活有关,对调节治疗反应有一定作用。基质金属蛋白酶-9
基因敲除的小鼠将被用来确定这种蛋白水解酶在光动力疗法结果中的作用。在具体目标3中,我们
将确定Survivin在肿瘤微环境中的表达和激活对光动力疗法的影响
响应性。表达野生型或显性负突变形式的基因修饰的肿瘤
Survivin将被用来确定这种凋亡抑制物在调节PDT肿瘤反应中的作用。
我们还将确定PDT与Hsp90/Survivin抑制剂17-AAG[17-AAG]联合使用的有效性。
(烯丙氨基)-17-去甲氧基格尔达霉素)。这些目标的成功实现将提供
PDT对肿瘤微环境和翻译数据调控的机制信息
需要证明PDT包括靶向抑制剂是合理的。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CHARLES Joseph GOMER其他文献
CHARLES Joseph GOMER的其他文献
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{{ truncateString('CHARLES Joseph GOMER', 18)}}的其他基金
Enhancing Photodynamic Therapy for Treating Kaposi's Sarcoma
加强光动力疗法治疗卡波西肉瘤
- 批准号:
7268113 - 财政年份:2006
- 资助金额:
$ 18.91万 - 项目类别:
Enhancing Photodynamic Therapy for Treating Kaposi's Sarcoma
加强光动力疗法治疗卡波西肉瘤
- 批准号:
7120420 - 财政年份:2006
- 资助金额:
$ 18.91万 - 项目类别:
Enhancing Photodynamic Therapy with COX-2 Inhibition
通过 COX-2 抑制增强光动力疗法
- 批准号:
6689681 - 财政年份:2003
- 资助金额:
$ 18.91万 - 项目类别:
Enhancing Photodynamic Therapy with COX-2 Inhibition
通过 COX-2 抑制增强光动力疗法
- 批准号:
7069612 - 财政年份:2003
- 资助金额:
$ 18.91万 - 项目类别:
Enhancing Photodynamic Therapy with COX-2 Inhibition
通过 COX-2 抑制增强光动力疗法
- 批准号:
6895347 - 财政年份:2003
- 资助金额:
$ 18.91万 - 项目类别:
Enhancing Photodynamic Therapy with COX-2 Inhibition
通过 COX-2 抑制增强光动力疗法
- 批准号:
6891828 - 财政年份:2003
- 资助金额:
$ 18.91万 - 项目类别:
Enhancing Photodynamic Therapy with COX-2 Inhibition
通过 COX-2 抑制增强光动力疗法
- 批准号:
6748582 - 财政年份:2003
- 资助金额:
$ 18.91万 - 项目类别:
Enhancing Photodynamic Therapy with COX-2 Inhibition
通过 COX-2 抑制增强光动力疗法
- 批准号:
6786437 - 财政年份:2003
- 资助金额:
$ 18.91万 - 项目类别:
Enhancing Photodynamic Therapy with COX-2 Inhibition
通过 COX-2 抑制增强光动力疗法
- 批准号:
7234259 - 财政年份:2003
- 资助金额:
$ 18.91万 - 项目类别:
PHOTOSENSITIZER LOCALIZATION IN PDT RESISTANT & PDT SENSITIVE CELLS
PDT 抗性中的光敏剂定位
- 批准号:
6308184 - 财政年份:2000
- 资助金额:
$ 18.91万 - 项目类别:
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