PDT: Mechanisms and Strategies for Optimization

PDT：优化机制和策略

• 批准号: 6747906
• 负责人: ALLAN R OSEROFF
• 金额: $ 213.22万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747906
• 关键词: clinical research; neoplasm /cancer pharmacology; neoplasm /cancer photoradiation therapy; pharmacokinetics; photochemistry; photosensitizing agents

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.

描述（由申请人提供）：该计划的总体目标与上一个资助期相同：它们是为了增加对光动力疗法（PDT）机制的理解并优化治疗。 该计划项目的统一假设是，如果没有一个有效的方法，光动力学癌症治疗的全部潜力就无法实现。 全面了解分子和细胞PDT反应的不同机制的相互作用。 该计划项目具有非常广泛，长期的，多学科的专业知识，是唯一有资格尝试开发这样一个全面的观点。 具体目标是：（i）设计和开发靶向肿瘤的光敏剂以优化功效和选择性;（ii）肿瘤微环境的PDT方案依赖性变化及其对调节对肿瘤生长重要的分子的后果的总体表征，特别是那些可能充当免疫系统的“危险信号”的分子;（iii）确定PDT改变适应性免疫应答的机制;（iv）优化反应预测方法，阐明临床注量率依赖的注量-反应关系，和临床翻译我们的临床前研究与不同的PDT方案。 四个单独的研究项目将解决以下问题： 1)光敏剂与半乳糖凝集素（在某些恶性细胞的细胞表面高度表达的蛋白质）的偶联能否提高PDT的选择性？ 2)PDT方案可以被设计为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微环境，它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诱导的适应性免疫变化的机制是什么？不同的PDT治疗方案如何影响这些变化？ 4)优化注量率和利用肿瘤反应预测方法能否提高基底细胞癌临床PDT治疗的疗效和选择性？生物反应调节剂能否改善治疗结果？ 这些项目得到三个科学核心的支持。