PDT: Mechanisms and Strategies for Optimization

描述(由申请者提供)：该计划的总体目标与上一个资助期相同：它们是为了加深对光动力疗法(PDT)机制的了解，并优化治疗。该计划项目的统一假设是，如果没有一个 全面了解分子和细胞光动力反应的不同机制的相互作用。该计划项目具有非常广泛的、长期的、多学科的专业知识，并且是唯一有资格尝试开发这样一个综合观点的项目。具体目标是：(I)设计和开发针对肿瘤的光敏剂，以优化疗效和选择性；(Ii)依赖PDT方案的全球表征；(Ii)肿瘤微环境的变化及其对调节肿瘤生长重要分子的后果，尤其是那些可能成为免疫系统“危险信号”的分子；(Iii)确定PDT改变适应性免疫反应的机制；(Iv)优化反应预测方法，阐明临床注入率依赖的通量-反应关系，以及我们使用不同PDT方案进行的临床前研究的临床翻译。四个单独的研究项目将解决以下问题： 1)光敏剂与Galectins的偶联能提高PDT的选择性吗？Galectins是某些恶性肿瘤细胞表面高表达的蛋白质。 2)PDT方案可以创造非常不同的肿瘤微环境(在氧合、细胞死亡途径和炎症方面)，并产生不同的分子肿瘤环境，如何影响抗肿瘤宿主反应；PDT如何影响肿瘤细胞对环境信号的反应能力？ 3)PDT诱导的获得性免疫改变的机制是什么？不同的PDT方案如何影响这些改变？ 4)优化剂量率和利用肿瘤反应预测方法能否提高临床PDT治疗基底细胞癌的疗效和选择性；生物反应调节剂能否改善治疗结果？ 这些项目得到了三个科学核心的支持。

DESCRIPTION (provided by applicant): The overall goals of this program remain the same as for the last funding period: they are to gain an increased understanding of the mechanisms of photodynamic therapy (PDT) and to optimize treatment. The unifying hypothesis of the Program Project is that the full potential of photodynamic cancer treatment 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, long-standing, multidisciplinary expertise and is uniquely qualified to attempt to develop such a comprehensive view. The specific goals are: (i) the design and development of photosensitizers targeted to the tumor to optimize efficacy and selectivity; (ii) the global characterization of PDT regimen dependent changes of the tumor microenvironment and their consequences for the regulation of molecules important for tumor growth, especially those that might act as "danger signals" for the immune system;(iii) the identification of mechanisms by which PDT alters the adaptive immune response; (iv) the optimization of response-predicting approaches, elucidation of clinical fluence rate dependent fluence-response relationships, and clinical translation of our preclinical studies with varying PDT regimens. Four individual research projects will address the following questions: 1) Can conjugation of photosensitizers to galectins, proteins that are highly expressed on the cell surface of certain malignant cells, improve PDT selectivity? 2) How does PDT regimen, which can be designed to create very different tumor microenvironments (in terms of oxygenation, cell death pathways and inflammation) and generate different molecular tumor milieus, influence the anti-tumor host response; how does PDT affect the capability of tumor cells to respond to environmental signals? 3) What are the mechanisms governing the PDT induced changes in adaptive immunity; how do different PDT regimens affect these changes? 4) Can optimizing fluence rates and utilizing tumor response-predicting approaches enhance efficacy and selectivity of clinical PDT treatment of basal cell carcinomas; can treatment outcomes be improved by biological response modifiers? The projects are supported by three scientific cores.