PDT - Mechanisms and Strategies for Optimization

PDT - 优化机制和策略

• 批准号: 7561813
• 负责人: BARBARA W. HENDERSON
• 金额: $ 220.39万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561813
• 关键词: PDT; Mechanisms; Strategies; Optimization

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. RELEVANCE (See instructions): This Program Project aims to discover, develop and translate into the clinical arena advances in photodynamic therapy (PDT) for the treatment of head and neck cancers, and non-melanoma skin cancers.

描述（由申请人提供）：该计划项目的统一特征仍然是其长期的从实验室到临床的方法：加深对光动力疗法（PDT）机制的了解并将其转化为优化的治疗。统一的假设是，如果不全面了解分子和细胞 PDT 反应的不同机制之间的相互作用，就无法充分发挥 PDT 治疗癌症的潜力。该计划项目拥有极其广泛的多学科专业知识，并且具有独特的资格来尝试形成如此全面的观点。具体目标是： (i) 发现和临床前开发光活化药物，这些药物缺乏长期的一般光毒性，并为治疗和诊断提供更大程度的功效和选择性； (ii) 分子和细胞机制的发现，可转化为改进光敏剂的设计和联合疗法的合理设计； (iii) 我们的发现的进一步开发、转化和临床应用，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，以支持局部PDT效应，并对恶性组织进行全身攻击； (iv) 开发治疗非黑色素瘤皮肤癌和 H&N 癌的新方法。五个单独的研究项目将解决以下问题：1）我们能否设计和开发基于焦脱镁叶绿酸（HPPH；665 nm）、红紫酰亚胺（700 nm）和细菌红紫酰亚胺（800 nm）的新型光敏剂和显像剂，并具有高效能和选择性？ 2）我们能否确定与决定肿瘤细胞PDT后存活相关的调控途径，并评估治疗干扰这些途径对控制肿瘤细胞生长复发的影响？ 3）我们能否了解PDT增强炎症增强抗肿瘤免疫的机制，并将我们的发现转化为临床以增强抗肿瘤免疫和对抗继发性疾病？ 4) 我们能否通过选择适当的治疗策略来优化非黑色素瘤皮肤癌的 ALA-PDT 治疗，其中考虑灌注和肿瘤内血管和光敏剂分布，了解机制并构建 PDT 计算模型？我们能否通过添加免疫调节剂和对接受 PDT 治疗的细胞进行疫苗接种来增强肿瘤控制？ 5) 第二代光敏HPPH PDT在控制早期口腔和喉癌方面是否等于或优于卟啉钠PDT，同时避免患者长期避免阳光照射？能否识别与治疗结果相关的生物标志物？这些项目由三个科学核心和一个行政核心支持。相关性（参见说明）：本计划旨在发现、开发用于治疗头颈癌和非黑色素瘤皮肤癌的光动力疗法 (PDT) 的进展并将其转化为临床领域的进展。