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: 8111512
• 负责人: Jonathan P Celli
• 金额: $ 8.89万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111512
• 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

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.

描述（由申请人提供）：该K99/R00建议的目的是开发一个新的翻译研究框架，从而特别利用机械性能在肿瘤生长和分子反应中的作用，专门用于设计新的光动力疗法（PDT）组合处理胰腺癌。先前的研究表明，尽管细胞外基质的刚度直接影响生长，发育和信号传导，但尚未探索该关键因素与治疗反应的相关性。这与胰腺的肿瘤特别相关，胰腺的肿瘤的特征是肿瘤周围密集的纤维组织的深刻生长（称为全腹膜）。为了克服我们的科学知识中的这一局限性，该提案引入了一种高度跨学科的方法，结合了1）荧光激光跟踪微流计量计（FLTM）一种新型的光学技术，以测量肿瘤中的机械性能（微流体学），肿瘤周围的机械性能（微流体学），2）使用可定制的三二维（3D）模型的模型NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN 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将PDT处理和特定生存因子作为基于机制的组合处理的潜在靶标，这些治疗是针对每个合成机械微环境定制的。然后，他将评估最有希望的组合处理的功效，以检验以下假设，即仅针对适当的机械微环境定制的治疗方法实际上才能在该环境中达成协同增强的功效。这项研究将在胰腺癌小鼠模型中测试最有前途的策略的最终结果。如果成功的话，这项研究不仅将为致命疾病产生新的治疗方法，而且还将增加新的理解水平，以指导可以应用于其他肿瘤研究的未来治疗方法的设计。已经组建了一个指导委员会，以指导K99阶段的研究，并促进Celli博士的培训。 PDT治疗癌症专家Tayyaba Hasan博士将在整个研究设计中提供主要的指导和指导。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（在他的实验室中开发），并有助于解释结果。 Nabeel Bardeesy博士和Stephen Pereira博士将提供分子生物学和胰腺癌治疗的培训。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。该奖项提供的机会不仅将允许Celli博士从事潜在的开创性研究，而且还将为他提供有价值的指导和培训，以对他作为独立研究员的职业生涯。 公共卫生相关性：拟议的研究与胰腺癌的治疗直接相关，并可能对其他实体瘤的应用有可能更广泛的应用。这项工作将为肿瘤基质的机械性能如何指导更有效的治疗策略的设计提供新的启示。在本研究中，该概念将特别利用来设计增强的光动力疗法组合治疗，这些疗法在转化为诊所后可能会直接影响这种致命的癌症患者的生存和生活质量。