Mechanism-based therapies for pancreatic cancer informed by stromal microrheology

基于基质微流变学的胰腺癌机制治疗

• 批准号: 8839208
• 负责人: Jonathan P Celli
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839208
• 关键词: Accounting; Adjuvant; Aftercare; Area; Award; Back; Biological; Biological Markers; Biological Models; Cancer Model; Cells; Clinic; Clinical; Clinical Trials; Coculture Techniques; Collagen; Combined Modality Therapy; Custom; Data; Data Set; Development; Disease; Dose; Encapsulated; Environment; Epidermal Growth Factor Receptor; Extracellular Matrix; Fibroblasts; Fluorescence; Future; Goals; Growth; Growth Factor; Growth and Development function; Heterogeneity; Image; Imaging technology; In Vitro; Integrins; Knowledge; LOX gene; Laboratories; Lasers; Lead; Light; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Measures; Mechanics; Mentors; Mentorship; Methods; Modeling; Modification; Molecular; Molecular Biology; Mus; Neoplasm Metastasis; Network-based; Optics; Outcome; Patients; Penetration; Pharmaceutical Preparations; Phase; Photochemotherapy; Process; Property; Protein-Lysine 6-Oxidase; Quality of life; Regimen; Regulatory Pathway; Reporting; Research; Research Design; Research Personnel; Resected; Residual Tumors; Rheology; Role; Schedule; Signal Transduction; Solid Neoplasm; Statistical Distributions; Technology; Testing; Therapeutic; Time; Tissues; Training; Translational Research; Translations; Treatment outcome; Tumor Biology; Tumor Volume; Tumor Weights; Validation; Work; antibody inhibitor; base; cancer therapy; career; crosslink; cytotoxic; design; fluorescence imaging; gemcitabine; in vitro Model; in vivo; insight; interdisciplinary approach; lymph nodes; malignant phenotype; mechanical drive; meetings; mouse model; nanofiber; neoplastic cell; novel; pancreatic neoplasm; programs; response; scaffold; small molecule; therapeutic development; therapy development; three-dimensional modeling; tool; treatment response; tumor; tumor growth; tumor microenvironment

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.

摘要/摘要 该K99/R00建议的目的是开发一个新的翻译研究框架，从而发挥作用 肿瘤生长和分子反应中的机械性能专门用于设计新的 胰腺癌的光动力疗法（PDT）联合治疗。先前的研究表明 而细胞周围细胞的细胞外基质的刚度直接影响生长，发展和 信号传导，该关键因素与治疗反应的相关性尚未探索。这是 与胰腺的肿瘤特别相关，其特征是密集纤维的深刻生长 肿瘤周围的组织（称为全鼻）。为了克服我们科学知识的限制， 该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 微型计量学（FLTM）一种新型的光学技术，用于测量机械性能（微型流变学） 2）使用合成纳米纤维的可自定义的三维（3D）肿瘤模型系统 脚手架称为puramatrix“带有可调矩阵力学，3）高通量定量成像 报告与基质机械性能有关的肿瘤生长特性和治疗反应的方法。 Celli博士将首先优化通过对原位panca的离体肿瘤的研究告知的3D模型系统 小鼠，评估基质流变学（通过FLTM和传统体积流变学测量）对生长和 发展3D体外肿瘤。他将进行PDT治疗和特定生存因子作为潜力 针对每个合成机械定制的基于机理的组合处理的目标 微环境。然后，他将评估最有希望的组合治疗的功效以测试 实际上，只有针对适当机械微环境定制的治疗的假设实际上才会 在该环境中实现协同增强的功效。这项研究将在测试测试方面达到高潮 胰腺癌小鼠模型中最有前途的策略。如果成功，这项研究不仅将 迫切需要为致命疾病产生新的治疗方法，但也会增加新的理解水平 指导可以应用于其他肿瘤的未来治疗方法的设计。指导 委员会已被组建为指导K99阶段的研究，并促进了Celli博士的培训。博士 PDT治疗癌症的专家Tayyaba Hasan将提供主要指导和指导 整体研究设计。彼得·彼得（Peter So）博士是新颖成像技术的世界专家。他将指导 Celli博士在FLTM测量中（是在他的实验室中开发的），并有助于解释结果。培训 Nabeel Bardeesy博士和博士将提供胰腺癌的分子生物学和治疗。 斯蒂芬·佩雷拉（Stephen Pereira）。加雷斯·麦金莱（Gareth McKinley）博士将提供流变学和微流行学的其他指导。这 该奖项提供的机会不仅允许Celli博士从事潜在的开创性研究，还可以 但还将为他提供有价值的指导和培训，以使他的职业生涯成为独立调查员。