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Physical Dynamics of Cancer Response to Chemotherapy in 3D Microenvironments

3D 微环境中癌症对化疗反应的物理动力学

基本信息

批准号：
9543230
负责人：
LISA Joy MCCAWLEY
金额：
$ 51.32万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9543230
关键词：
Acidity Address Adverse effects Affect Apoptosis Biomedical Engineering Biopsy Biopsy Specimen Bioreactors Breast Breast Cancer cell line Cell Culture Techniques Cell Line Cellular Spheroids Chemicals Clinical assessments Complex Computer Simulation Coupled Development Dimensions Disease Dose Engineering Experimental Models Exposure to Extracellular Matrix Feedback Goals Growth Growth and Development function Human In Vitro Intercellular Fluid Lab-On-A-Chips Malignant Neoplasms Mammary Neoplasms Measurement Metabolic Methodology Methods Microfluidic Microchips Modeling Monitor Morphology Necrosis Normal tissue morphology Nutrient Organoids Outcome Outcome Study Patients Pattern Pharmaceutical Preparations Pharmacotherapy Prediction of Response to Therapy Primary Neoplasm Property Resolution Running System Technology Therapeutic Thick Tissues Tracer Tumor Tissue Tumor-Derived anticancer treatment base chemotherapy design drug efficacy improved in vitro Model in vivo in vivo Model malignant breast neoplasm mathematical model novel organ on a chip personalized predictions personalized therapeutic physical science pre-clinical predictive test pressure public health relevance reconstruction response senescence simulation therapeutic development three dimensional cell culture treatment response tumor tumor growth tumor microenvironment tumorigenic

项目摘要

DESCRIPTION (provided by applicant): These studies aim to develop a new computationally driven platform to examine complex physical and chemical microenvironments utilizing organ-on-chip microfluidic bioreactor technology coupled with a predictive mathematical model of tumor growth and therapeutic response. Malignant breast tumors are highly heterogeneous in terms of their cellular composition, varying levels of oxygenation, acidity, and nutrients, as well as local changes in the extracellular matrix. Furthermore, tumor tissue and tumor microenvironment properties can dynamically evolve not only during tumor growth but also when anticancer treatments are administered. Despite this, nearly all pre-clinical assessments of drug efficacy and optimal dosing are performed using homogeneous 2D cell cultures that do not resemble the cellular, metabolic, and physical features manifest in tumors in vivo. Such approach suffered from overly reductionist ex vivo / in vitro studies may not fully recapitulate th complexity of cancers especially the physical and chemical microenvironment. To address these issues we propose to develop an integrated quantitative platform that combines the power of organ-on-chip 3D tissue bioreactor, developed to include non-uniform fully controlled physical and chemical microenvironments, together with a 3DMultiCel math model that allows predictive testing of a broad range of microenvironmental combinations around the experimentally validated baseline. To achieve this goal in a quantitative way we have formed a transdisciplinary team consisting of cancer biologists, biomedical engineers and mathematicians, who will develop an experimental platform for individualized anticancer treatment based on physical science principles. Our long-term goal is to provide a computationally driven "lab-on-chip" platform for 3D organotypic cultures derived from patients' tumor biopsies that will be exposed to fully controlled but dynamically variable microenvironments that will be used to optimize personalized therapeutic treatments that effectively provoke breast tumor regression with minimized harmful side effects for surrounding normal tissue. Outcomes of this study will be: (i) an improved experimental platform that combines 3D culture of tumor organoids coupled with validated predictive mathematical models for the growth and response of human breast tumor organoids within realistic microenvironments; and (ii) quantitative methods that allow one to assess the dynamics of breast tumor organoid development and response to anti-tumor treatments, using mathematical modeling. Our aims are: 1. Develop a predictive methodology to assess effects of defined microenvironments on the dynamics of normal and tumorigenic breast organoids and their sensitivity to therapeutics; 2. Construct and validate in silico model-guided complex spatial and temporal microenvironmental gradients established within TTb-G reactor, and assess breast tumor organoids response to chemotherapeutics. 3. Apply our integrated computational/engineering approach to guide therapy and predict therapeutic response ex vivo and in vivo.