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提案的目标是开发一个新的转化研究框架，其中机械特性在肿瘤生长和分子反应中的作用被专门利用来设计新的光动力治疗（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细胞的生长、发育和信号传导，但这一关键因素与治疗反应的相关性尚未得到探讨。这与胰腺肿瘤特别相关，其特征是肿瘤周围致密纤维组织的深度生长（称为纤维组织增生）。为了克服我们科学知识中的这一局限，本建议引入了一种高度跨学科的方法，结合1)荧光激光跟踪微流变（FLTM），一种用于测量肿瘤内部和周围机械特性（微流变学）的新型光学技术，2)可定制的三维（3D）肿瘤模型系统，该系统使用一种称为PuraMatrix的合成纳米纤维支架，具有可调矩阵力学，3)一种高通量定量成像方法来报告肿瘤生长特性和治疗反应与基质力学特性的关系。Celli博士将首先通过对原位PanCa小鼠离体肿瘤的研究来优化3D模型系统，以评估基质流变学（通过FLTM和传统体流变学测量）对体外3D肿瘤生长和发展的影响。他将进行PDT治疗和特定生存因素作为潜在目标，针对每个合成机械微环境定制基于机制的联合治疗。然后，他将评估最有希望的联合治疗的疗效，以验证一个假设，即只有针对适当的机械微环境定制的治疗才能在该环境中实现协同增强的疗效。这项研究最终将在胰腺癌小鼠模型中测试最有希望的策略。如果成功，这项研究不仅将为这种致命疾病提供急需的新治疗方法，而且还将为指导未来治疗方法的设计增加一个新的认识水平，这些治疗方法可以应用于其他肿瘤的研究。一个指导委员会已经成立，以指导K99阶段的研究，并促进Celli博士的培训。Tayyaba Hasan博士是PDT治疗癌症的专家，他将在整个研究设计中提供主要的指导和指导。Peter So博士是新型成像技术领域的世界级专家。他将指导Celli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流变学方面提供额外的指导。该奖项提供的机会不仅将使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研究者的职业生涯提供宝贵的指导和培训。