Mechanism-based therapies for pancreatic cancer informed by stromal microrheology

摘要/总结 这个K99/R 00提案的目标是开发一个新的翻译研究框架， 肿瘤生长和分子反应中的机械特性被专门用于设计新的 光动力疗法（PDT）组合治疗胰腺癌。以前的研究已经表明 而细胞周围的细胞外基质的刚性直接影响细胞的生长、发育 信号，这一关键因素与治疗反应的相关性尚未被探索。这是 尤其与胰腺肿瘤相关，胰腺肿瘤的特征在于致密纤维组织的深度生长， 肿瘤周围的组织（称为去上皮组织增生）。为了克服我们科学知识的这一局限性， 该提议引入了高度跨学科的方法，其结合1）荧光激光跟踪 微观流变学（FLTM）是一种测量材料力学性能（微观流变学）的新型光学技术， 和肿瘤周围，2）使用合成的纳米颗粒的可定制的三维（3D）肿瘤模型系统， 支架称为PuraMatrix”与可调矩阵力学，3）高通量定量成像 报告肿瘤生长特性和与基质机械特性相关的治疗反应的方法。 博士Celli将首先优化3D模型系统，该系统由原位PanCa的离体肿瘤研究提供信息。 小鼠，以评估基质流变学（通过FLTM和传统的整体流变学测量）对生长的影响， 3D体外肿瘤的发展。他将进行PDT治疗和特定的生存因素作为潜在的 针对每种合成机械的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定制的治疗实际上 在该环境中实现协同增强的功效。这项研究将在测试 在胰腺癌小鼠模型中最有前途的策略。如果成功，这项研究不仅 为一种致命疾病生产急需的新疗法，但也将增加一个新的理解水平， 以指导未来治疗方法的设计，这些治疗方法可应用于其他肿瘤的研究。一个辅导 委员会已经成立，以指导K99阶段的研究，并促进Celli博士的培训。博士 Tayyaba Hasan是PDT治疗癌症的专家，他将提供主要的指导和指导， 整体研究设计。共同导师Peter So博士是新型成像技术的世界专家。他要引导 博士Celli在FLTM测量（这是在他的实验室开发），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。加雷斯·麦金利博士将提供流变学和微观流变学方面的额外指导。的 该奖项提供的机会不仅使Celli博士能够从事潜在的突破性研究， 而且还将为他作为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.