PDT - Mechanisms and Strategies for Optimization

PDT - 优化机制和策略

• 批准号: 8462208
• 负责人: BARBARA W. HENDERSON
• 金额: $ 195.41万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462208
• 关键词: Address; Biological Markers; Blood Vessels; Cancer Vaccines; Cells; Clinic; Clinical; Combined Modality Therapy; Computer Simulation; Development; Diagnosis; Disease; Exhibits; Generations; Goals; HPPH; Head and Neck Cancer; Image; Immune; Immune response; Individual; Inflammation; Instruction; Larynx; Malignant - descriptor; Malignant Neoplasms; Molecular; Oral cavity; Pathway interactions; Patients; Perfusion; Photochemotherapy; Photosensitizing Agents; Phototoxicity; Porfimer Sodium; Qualifying; Recurrence; Regulatory Pathway; Research Project Grants; Skin Carcinoma; The Sun; Therapeutic; Tissues; Translating; Translations; Treatment outcome; Tumor Immunity; Vaccination; base; bench to bedside; cell growth; clinical application; combat; design; improved; multidisciplinary; neoplastic cell; novel; novel strategies; pre-clinical; programs; response; treatment strategy; tumor

DESCRIPTION (provided by applicant): The unifying feature of this Program Project remains its long-standing bench to bedside approach: to gain an increased understanding of photodynamic therapy (PDT) mechanisms and to translate it into optimized treatment. The unifying hypothesis is that the full potential of PDT of cancer cannot be realized without a comprehensive understanding of the interaction of the diverse mechanisms of molecular and cellular PDT responses. This Program Project has exceptionally broad, multidisciplinary expertise and is uniquely qualified to attempt to develop such a comprehensive view. The specific goals are: (i) The discovery and preclinical development of photoactivatable agents that lack prolonged general phototoxicity and provide a greater degree of efficacy and selectivity for treatment as well as diagnosis; (ii) The discovery of molecular and cellular mechanisms that can be translated into the design of improved photosensitizers and the rational design of combination therapies; (iii) The further development, translation and clinical application of our discovery that PDT and PDT generated anti-tumor vaccines can stimulate the adaptive anti-cancer immune response to support the local PDT effect with a systemic attack on the malignant tissue; (iv) The development of novel approaches to the treatment of non-melanoma skin cancer and H&N cancer. Five individual research projects will address the following questions: 1) Can we design and develop novel photosensitizing and imaging agents based on pyropheophorbides (HPPH; 665 nm), purpurinimides (700 nm) and bacterio-purpurinimides (800 nm) that exhibit high efficacy and selectivity? 2) Can we identify regulatory pathways that are relevant in determining post-PDT survival of tumor cells and assess the impact of therapeutic interference with these pathways in controlling recurrence of tumor cell growth? 3) Can we understand the mechanisms by which PDT enhanced inflammation augments anti-tumor immunity and translate our findings to the clinic to enhance anti-tumor immunity and combat secondary disease? 4) Can we optimize the ALA-PDT treatment of non-melanoma skin cancer by choosing appropriate treatment strategies that consider perfusion and intra-tumor vascular and photosensitizer distributions, understanding mechanisms and constructing computational models for PDT? Can we enhance tumor control through addition of immune modulators and vaccination of patients with PDT treated cells? 5) Is PDT with the second generation photosensitize HPPH equal or superior to porfimer sodium PDT in controlling early cancer of the oral cavity and larynx, while sparing patients protracted sun avoidance? Can biomarkers be identified that correlate with treatment outcome? The projects are supported by three scientific cores and an Administrative Core.

描述（由申请人提供）：该计划项目的统一特征仍然是其长期存在的床边方法：以增加对光动力疗法（PDT）机制的了解，并将其转化为优化的治疗方法。统一的假设是，如果没有对分子和细胞PDT反应的各种机制的相互作用的全面了解，则无法实现癌症的全部潜力。该计划项目具有非常广泛的多学科专业知识，并且具有独特的资格，可以尝试发展这种全面的观点。具体目标是：（i）缺乏延长一般光毒性的光活化药物的发现和临床前开发，并为治疗和诊断提供了更大程度的疗效和选择性； （ii）发现分子和细胞机制，可以转化为改进的光敏剂的设计和组合疗法的合理设计； （iii）我们发现的进一步发展，翻译和临床应用，即PDT和PDT产生的抗肿瘤疫苗可以刺激适应性抗癌免疫反应，以通过对恶性组织的系统性攻击来支持局部PDT效应； （iv）开发了治疗非黑色素瘤皮肤癌和H＆N癌症的新方法。五个单独的研究项目将解决以下问题：1）我们是否可以根据焦磷酸酯（HPPH; 665 nm），紫脂蛋白酰亚胺（700 nm）和细菌 - 吡啶胺（800 nm）设计和开发新颖的光敏和成像剂，表现出高效率和选择性？ 2）我们是否可以确定与确定肿瘤细胞生存后生存相关的调节途径，并评估治疗性干扰这些途径在控制肿瘤细胞生长复发方面的影响吗？ 3）我们能否理解PDT增强炎症的机制增强了抗肿瘤免疫力并将我们的发现转化为诊所以增强抗肿瘤免疫力和战斗次要疾病？ 4）我们可以通过选择考虑灌注和肿瘤内血管和光敏剂分布的适当治疗策略来优化非黑色素瘤皮肤癌的ALA-PDT治疗，了解机制并为PDT构建计算模型吗？我们可以通过添加免疫调节剂和PDT治疗细胞患者的疫苗接种来增强肿瘤控制吗？ 5）在控制口腔和母乳的早期癌症时，PDT具有第二代光敏性HPPH相等或优于Porfimer钠PDT，而避免了太阳避免太阳？可以确定与治疗结果相关的生物标志物吗？这些项目得到了三个科学核心和一个行政核心的支持。