Mechanism-based therapies for pancreatic cancer informed by stromal microrheology

描述(申请人提供)：这项K99/R00提案的目标是开发一种新的转译研究框架，从而专门利用机械特性在肿瘤生长和分子反应中的作用来设计新的光动力疗法(PDT)联合治疗胰腺癌。先前的研究表明，虽然细胞周围细胞外基质的刚性直接影响生长、发育和信号转导，但这一关键因素与治疗反应的相关性尚未被探索。这与胰腺肿瘤尤其相关，胰腺肿瘤的特征是肿瘤周围致密的纤维组织大量生长(称为结缔组织增生症)。为了克服我们科学知识中的这一限制，本建议引入了一种高度跨学科的方法，结合了1)荧光激光跟踪显微流变学(FlTM)--一种新的光学技术来测量肿瘤内及周围的机械特性(微观流变学)，2)一个可定制的三维(3D)肿瘤模型系统，该系统使用名为PuraMatrix的合成纳米纤维支架以及可调的基质力学，3)高通量定量成像方法，以报告肿瘤的生长特性和与基质力学特性相关的治疗反应。Celli博士将首先优化3D模型系统，以了解来自原位panca小鼠的体外肿瘤研究，以评估基质流变学(由FLTM和传统的整体流变学测量)对3D体外肿瘤生长和发展的影响。他将进行PDT治疗和特定的生存因素，作为基于机制的联合治疗的潜在目标，这些联合治疗是为每个合成机械微环境定制的。然后，他将评估最有希望的联合治疗的疗效，以检验这样的假设，即只有针对适当的机械微环境定制的治疗实际上才能在该环境中实现协同增强的疗效。这项研究将在小鼠胰腺癌模型上测试最有希望的策略。如果成功，这项研究不仅将为一种致命疾病提供急需的新疗法，还将增加新的认识水平，以指导未来可应用于其他肿瘤研究的治疗方法的设计。已经成立了一个指导委员会来指导K99阶段的研究，并为切利博士的培训提供便利。塔亚巴·哈桑博士是光动力疗法治疗癌症的专家，他将在整个研究设计中提供主要指导和指导。合作导师苏永明博士是新型成像技术领域的世界专家。他将指导塞利博士进行FLTM测量(这是在他的实验室开发的)，并帮助解释结果。Nabeel Bardeesy博士和Stephen Pereira博士将提供胰腺癌分子生物学和治疗方面的培训。Gareth McKinley博士将在流变学和微观流变学方面提供额外的指导。该奖项提供的机会不仅将使切利博士能够从事可能具有开创性的研究，还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。 公共卫生相关性：拟议的研究与胰腺癌的治疗直接相关，并有可能更广泛地应用于其他实体肿瘤。这项工作将为肿瘤间质的机械特性如何指导更有效的治疗策略的设计提供新的线索。在目前的研究中，这一概念将被特别用于设计增强型光动力疗法联合疗法，一旦转化到临床，可能会对这种致命癌症患者的生存和生活质量产生直接影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed research is directly relevant to the treatment of pancreatic cancer with potentially broader application to other solid tumors. This work will shed new light on how the mechanical properties of the tumor stroma can guide the design of more effective therapeutic strategies. In the present study this concept will specifically be leveraged to design enhanced photodynamic therapy combination treatments which, upon translation into the clinic, could have a direct impact on survival and quality of life for patients with this lethal form of cancer.