PDT - Mechanisms and Strategies for Optimization

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从工作台到床边的方法：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反应的不同机制的相互作用，就不可能实现癌症的PDT的全部潜力。该计划项目拥有极其广泛的多学科专业知识，是尝试开发这样一个全面观点的唯一合格的项目。具体目标是：(I)发现和临床前开发缺乏持久的一般光毒性的光激活剂，并为治疗和诊断提供更大程度的有效性和选择性；(Ii)发现可转化为改进的光敏剂设计和合理组合疗法的分子和细胞机制；(Iii)我们发现的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，对恶性组织进行系统性攻击；(4)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(HPPH)的新型光敏剂和显像剂；2)我们能否识别决定肿瘤细胞PDT后存活率的相关调控通路，并评估治疗干预对控制肿瘤细胞复发的影响？3)我们能否了解PDT增强炎症增强抗肿瘤免疫的机制，并将我们的研究结果应用于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ALA-PDT治疗非黑色素瘤皮肤癌，考虑到灌注和肿瘤内血管和光敏剂的分布，理解光动力疗法的机理和构建计算模型？我们能否通过增加免疫调节剂和接种PDT治疗细胞的患者来增强肿瘤控制？5)在控制口腔和喉部早期癌症方面，第二代光敏剂HPPH的PDT是否等同于或优于Porfmer Na PDT，同时避免患者长时间避光？能否确定与治疗结果相关的生物标记物？这些项目得到三个科学核心和一个行政核心的支持。

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.