Mechanism-based therapies for pancreatic cancer informed by stromal microrheology

摘要/摘要 这项K99/R00提案的目标是开发一个新的翻译研究框架，从而使 在肿瘤生长和分子反应方面的力学特性被专门利用来设计新的 光动力疗法(PDT)联合治疗胰腺癌。此前的研究表明， 而细胞周围细胞外基质的刚性直接影响细胞的生长、发育和 作为信号，这一关键因素与治疗反应的相关性尚未被探索。这是 尤其适用于胰腺肿瘤，其特征是大量致密的纤维生长 肿瘤周围组织(称为结缔组织增生症)。为了克服我们科学知识中的这一局限， 这项建议引入了一种高度跨学科的方法，结合了1)荧光激光跟踪 微流变学是一种测量材料力学性能(微流变学)的新光学技术 和肿瘤周围，2)使用合成纳米纤维的可定制三维(3D)肿瘤模型系统 名为PuraMatrix的支架具有可调的矩阵力学，3)高通量定量成像 报告与基质机械特性相关的肿瘤生长特性和治疗反应的方法。 Celli博士将首先优化3D模型系统，以了解对来自原位胰腺的体外肿瘤的研究 为评估基质流变学(用FLTM和传统的整体流变学测量)对小鼠生长和 三维体外肿瘤的研究进展。他将进行PDT治疗和潜在的特定生存因素 为每种合成机械定制的基于机械的组合治疗的目标 微环境。然后，他将评估最有希望的联合治疗的疗效，以测试 假设只有为适当的机械微环境量身定做的治疗才能事实上 在这种环境中实现协同增强的功效。这项研究的最终结果将是对 在胰腺癌小鼠模型中最有希望的策略。如果成功，这项研究不仅将 为一种致命疾病产生急需的新疗法，但也将增加新的理解水平 以指导未来治疗方案的设计，可应用于其他肿瘤的研究。一次辅导 已经成立了一个委员会来指导K99阶段的研究，并为切利博士的培训提供便利。Dr。 塔亚巴·哈桑是光动力疗法治疗癌症的专家，他将在 总体研究设计。合作导师苏永明博士是新型成像技术领域的世界专家。他将会引导 Celli博士参与了FLTM测量(这是在他的实验室开发的)，并帮助解释结果。培训 胰腺癌的分子生物学和治疗将由Nabeel Bardeesy博士和Dr。 斯蒂芬·佩雷拉。Gareth McKinley博士将在流变学和微观流变学方面提供额外的指导。这个 这一奖项提供的机会不仅将使切利博士能够进行潜在的开创性研究， 但也将为他作为一名独立调查员的职业生涯提供宝贵的指导和培训。

ABSTRACT/SUMMARY The goal of this K99/R00 proposal is to develop a new translational research framework whereby the role of the mechanical properties in tumor growth and molecular response are specifically exploited to design new photodynamic therapy (PDT) combination treatments for pancreatic cancer. Previous studies have shown that while the rigidity of the extracellular matrix surrounding cells directly impacts growth, development and signaling, the relevance of this crucial factor to treatment response has not yet been explored. This is particularly relevant for tumors of the pancreas which are characterized by a profound growth of dense fibrous tissue around the tumor (called desomplasia). In order to overcome this limitation in our scientific knowledge, this proposal introduces a highly interdisciplinary approach combining 1) fluorescence laser tracking microrheometry (FLTM) a novel optical technology to measure the mechanical properties (microrheology) in and around tumors, 2) a customizable three-dimensional (3D) tumor model system using a synthetic nanofiber scaffold called PuraMatrix" with tunable matrix mechanics, 3) a high-throughput quantitative imaging approach to report tumor growth properties and treatment response in relation to matrix mechanical properties. Dr. Celli will first optimize the 3D model system informed by studies on ex vivo tumors from orthotopic PanCa mice, to assess the impact of matrix rheology (measured by FLTM and traditional bulk rheology) on growth and development of 3D in vitro tumors. He will conduct PDT treatments and specific survival factors as potential targets for mechanism based combination treatments that are customized to each synthetic mechanical microenvironment. He will then evaluate the efficacy of the most promising combination treatments to test the hypothesis that only a treatment customized for the appropriate mechanical microenvironment will in fact achieve a synergistically enhanced efficacy in that environment. The research will culminate in testing of the most promising strategies in a mouse model of pancreatic cancer. If successful, this research will not only produce urgently needed new treatments for a deadly disease, but will also add a new level of understanding to guide the design of future treatments which could be applied to the study of other tumors. A mentoring committee has been assembled to guide the research in the K99 phase and facilitate Dr. Celli's training. Dr. Tayyaba Hasan, who is an expert in PDT treatment of cancer will provide primary mentorship and guidance in the overall study design. Co-Mentor, Dr. Peter So is a world expert in novel imaging technologies. He will guide Dr. Celli in FLTM measurements (which was developed in his laboratory) and help interpret results. Training in the molecular biology and treatment of pancreatic cancer will be provided by Dr. Nabeel Bardeesy and Dr. Stephen Pereira. Dr. Gareth McKinley will provide additional mentorship in rheology and microrheology. The opportunities provided by this award will not only allow Dr. Celli to pursue potentially ground-breaking research, but will also provide him with valuable mentorship and training to his career as an independent investigator.