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

基本信息

批准号：
8310211
负责人：
Jonathan P Celli
金额：
$ 14.4万
依托单位：
UNIVERSITY OF MASSACHUSETTS BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8310211
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

项目摘要

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.

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，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）组合疗法胰腺癌。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、发育和信号传导，但这一关键因素与治疗反应的相关性尚未被探索。这对于胰腺肿瘤尤其重要，胰腺肿瘤的特点是肿瘤周围致密纤维组织深度生长（称为去组织增生）。为了克服我们科学知识中的这一限制，本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) 一种新颖的光学技术，用于测量肿瘤内部和周围的机械特性（微流变学），2) 一种可定制的三种技术三维（3D）肿瘤模型系统，使用名为 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，用于报告肿瘤生长特性和与基质机械特性相关的治疗反应。 Celli 将首先根据原位 PanCa 小鼠离体肿瘤的研究优化 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 3D 体外肿瘤生长和发育的影响。治疗和特定生存因素作为基于机制的组合治疗的潜在目标，这些组合治疗针对每个合成机械微环境进行定制。然后，他将评估最有希望的组合治疗的功效，以检验这样的假设：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功效。该研究最终将在胰腺癌小鼠模型中测试最有前途的策略。如果成功，这项研究不仅将为致命疾病提供急需的新疗法，而且还将增加新的理解水平，以指导未来疗法的设计，这些疗法可应用于其他肿瘤的研究。已经组建了一个指导委员会来指导 K99 阶段的研究并促进 Celli 博士的培训。 Tayyaba Hasan 博士是癌症 PDT 治疗专家，他将为整个研究设计提供主要指导和指导。共同导师 Peter So 博士是新型成像技术领域的世界专家。他将指导 Celli 博士进行 FLTM 测量（由他的实验室开发）并帮助解释结果。 Nabeel Bardeesy 博士和 Stephen Pereira 博士将提供分子生物学和胰腺癌治疗方面的培训。 Gareth McKinley 博士将提供流变学和微流变学方面的额外指导。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，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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Image-Based Quantification of Benzoporphyrin Derivative Uptake, Localization, and Photobleaching in 3D Tumor Models, for Optimization of PDT Parameters.

对 3D 肿瘤模型中苯并卟啉衍生物的摄取、定位和光漂白进行基于图像的定量，以优化 PDT 参数。

DOI：
发表时间：
2012
期刊：
影响因子：
12.4
作者：
Glidden, Michael D;Celli, Jonathan P;Massodi, Iqbal;Rizvi, Imran;Pogue, Brian W;Hasan, Tayyaba
通讯作者：
Hasan, Tayyaba

PDT dose parameters impact tumoricidal durability and cell death pathways in a 3D ovarian cancer model.

PDT 剂量参数影响 3D 卵巢癌模型中的杀瘤持久性和细胞死亡途径。

DOI：
发表时间：
2013-07
期刊：
影响因子：
3.3
作者：
Rizvi, Imran;Anbil, Sriram;Alagic, Nermina;Celli, Jonathan;Celli, Jonathan P;Zheng, Lei Zak;Palanisami, Akilan;Glidden, Michael D;Pogue, Brian W;Hasan, Tayyaba
通讯作者：
Hasan, Tayyaba

Longitudinal measurement of extracellular matrix rigidity in 3D tumor models using particle-tracking microrheology.

使用粒子跟踪微流变学纵向测量 3D 肿瘤模型中的细胞外基质刚性。