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: 8702320
• 负责人: Jonathan P Celli
• 金额: $ 23.4万
• 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/8702320
• 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/总结 K99/R00 提案的目标是开发一个新的转化研究框架，其中 专门利用肿瘤生长和分子反应的机械特性来设计新的 胰腺癌的光动力疗法（PDT）联合治疗。先前的研究表明 而细胞周围细胞外基质的刚性直接影响细胞的生长、发育和发育。 信号传导，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，其特点是致密纤维的深度生长 肿瘤周围的组织（称为去发育）。为了克服我们科学知识的局限性， 该提案引入了一种高度跨学科的方法，结合了 1) 荧光激光跟踪 微流变测量 (FLTM) 是一种新型光学技术，用于测量机械性能（微流变学） 围绕肿瘤，2) 使用合成纳米纤维的可定制三维 (3D) 肿瘤模型系统 称为“PuraMatrix”的支架，具有可调矩阵力学，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。 Celli 博士将首先优化来自原位 PanCa 的离体肿瘤研究的 3D 模型系统 小鼠，评估基质流变学（通过 FLTM 和传统本体流变学测量）对生长和生长的影响 3D 体外肿瘤的发育。他将进行 PDT 治疗并尽可能考虑特定的生存因素 基于机制的组合治疗目标，针对每种合成机械进行定制 微环境。然后，他将评估最有希望的联合治疗的疗效，以测试 假设只有针对适当的机械微环境定制的治疗实际上才会 在该环境中实现协同增强的功效。该研究最终将测试 胰腺癌小鼠模型中最有前途的策略。如果成功的话，这项研究不仅将 为一种致命疾病提供急需的新疗法，同时也将增加新的理解水平 指导未来治疗的设计，这些治疗可应用于其他肿瘤的研究。一个辅导 委员会已成立，以指导 K99 阶段的研究并促进 Celli 博士的培训。博士。 Tayyaba Hasan 是癌症 PDT 治疗专家，他将提供主要指导和指导 总体研究设计。共同导师 Peter So 博士是新型成像技术领域的世界专家。他会指导 Celli 博士负责 FLTM 测量（由他的实验室开发）并帮助解释结果。培训于 胰腺癌的分子生物学和治疗将由 Nabeel Bardeesy 博士和 Dr. 史蒂芬·佩雷拉. Gareth McKinley 博士将提供流变学和微流变学方面的额外指导。这 该奖项提供的机会不仅使塞利博士能够从事潜在的突破性研究， 但也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。