PDT - Mechanisms and Strategies for Optimization

描述（由申请人提供）：该项目的统一特点仍然是其长期的从实验到临床的方法：增加对光动力疗法（PDT）机制的理解，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反应的多种机制之间的相互作用，就无法实现癌症PDT的全部潜力。该项目具有非常广泛的多学科专业知识，是唯一有资格尝试发展这样一个全面的观点。具体目标是：(i)发现和临床前开发不具有长期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；发现分子和细胞机制，可用于设计改进的光敏剂和合理设计联合疗法；（iii） PDT和PDT生成的抗肿瘤疫苗的进一步开发、转化和临床应用，可以刺激适应性抗癌免疫反应，支持局部PDT效应，对恶性组织进行系统性攻击；（iv）开发治疗非黑色素瘤皮肤癌和H&N癌的新方法。5个单独的研究项目将解决以下问题：1)我们是否可以设计和开发基于高效率和选择性的新型光敏和显像剂，这些光敏和显像剂是基于邻苯二甲酸酯（HPPH; 665 nm）、紫外光酰亚胺（700 nm）和细菌-紫外光酰亚胺（800 nm）的？2)我们能否确定与pdt后肿瘤细胞存活相关的调控通路，并评估治疗干预这些通路对控制肿瘤细胞生长复发的影响？3)我们能否理解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)考虑灌注、肿瘤内血管和光敏剂分布，选择合适的治疗策略，了解PDT的作用机制，构建PDT的计算模型，能否优化ALA-PDT对非黑色素瘤皮肤癌的治疗？我们可以通过添加免疫调节剂和接种PDT治疗细胞的患者来加强肿瘤控制吗？5)第二代光敏性HPPH的PDT在控制早期口腔癌和喉癌的疗效上是否等于或优于porfimer钠PDT，同时避免患者长期避光？是否可以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。

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.