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工作台到床边的方法：获得对光动力学治疗（PDT）机制的更多了解，并将其转化为优化的治疗。统一的假设是，如果没有对分子和细胞PDT反应的不同机制的相互作用的全面理解，就不能实现PDT治疗癌症的全部潜力。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来尝试开发这样一个全面的观点。具体目标是：（一）发现和临床前研制可光活化的药剂，这些药剂没有长期的一般光毒性，并为治疗和诊断提供更大程度的效力和选择性;（二）发现可转化为改进光敏剂设计和合理设计综合疗法的分子和细胞机制;（iii）进一步发展、转化和临床应用我们的发现，即PDT和PDT产生的抗肿瘤疫苗可以刺激适应性抗癌免疫应答，以支持局部PDT效应，对恶性组织进行系统攻击;（四）开发治疗非黑色素瘤皮肤癌和H&N癌症的新方法。五个独立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），红嘌呤酰亚胺（700 nm）和细菌红嘌呤酰亚胺（800 nm），表现出高效率和高选择性的新型光敏和成像剂？2)我们能否确定与PDT后肿瘤细胞存活相关的调控途径，并评估治疗干预对这些途径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)我们是否可以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，这些治疗策略考虑了灌注和肿瘤内血管和光敏剂分布，了解PDT的机制并构建PDT的计算模型？我们能否通过添加免疫调节剂和给患者接种PDT处理的细胞来增强肿瘤控制？5)光动力疗法联合第二代光敏剂HPPH治疗口腔和喉早期癌与单纯光动力疗法相比，是否具有相同或上级的疗效，同时避免了患者长时间的避光？是否可以识别与治疗结果相关的生物标志物？这些项目得到三个科学核心和一个行政核心的支持。相关性（参见说明）：本计划项目旨在发现、开发和转化光动力疗法（PDT）治疗头颈癌和非黑色素瘤皮肤癌的临床竞技场进展。

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.