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All-Human Microphysical Model of Metastasis Therapy

转移治疗的全人类微物理模型

基本信息

批准号：
9308162
负责人：
LINDA G GRIFFITH
金额：
$ 7.73万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2012-07-24 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308162
关键词：
Affect Animal Model Behavior Biological Biological Models Bioreactors Breast Carcinoma Cell Cycle Stage Cells Circadian Rhythms Colorectal Complex Development Disease Disseminated Malignant Neoplasm Disseminated carcinoma Distant Dose Drainage procedure Engineering Environment Event Excision Fostering Functional disorder Gastrointestinal tract structure Hormonal Hormone use Hormones Hour Human In Situ In Vitro Inflammation Inflammatory Infusion procedures Knowledge Link Liver Lung Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Measures Metabolic Metabolic Pathway Metabolism Metastatic Neoplasm to the Liver Modeling Molecular Monitor Morbidity - disease rate Neoplasm Metastasis Nodule Nutrient Operative Surgical Procedures Organ Pancreas Performance Pharmaceutical Preparations Physiological Primary Neoplasm Property Prostate Resistance Signal Pathway Signal Transduction Site Solid Neoplasm Spleen Structure of aggregated lymphoid follicle of small intestine System Systemic Therapy Technology Testing Therapeutic Time Tissues Toxic effect Treatment-related toxicity Tumor Biology Tumor Markers cell behavior chemotherapeutic agent chemotherapy clinically relevant cytokine design drug development drug efficacy drug metabolism drug modification drug testing experience host neoplasm interaction in vitro Model in vivo kinase inhibitor liver function microsystems mimicry mortality neoplastic cell next generation novel strategies novel therapeutics programs response technology development tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): All-Human Microphysical Model of Metastasis Therapy Successful eradication of metastatic disease remains the grand challenge in reducing mortality from solid tumors. Although ablative approaches are infrequently possible, systemic chemotherapy usually is the only feasible option for inhibiting progression and increasing survival time, though it is rarely curative. Our understanding of why chemotherapeutic agents fail to eliminate metastases, and our ability to create more effective therapeutic strategies, is limited by both our deficit in dissecting the tumor-host interactions at a molecular and cellular level, and a lack of relevant model systems to screen novel therapies; and a dearth of all human systems to do this in a relevant manner. There is evidence that the tumor cells are affected by the metastatic micro-environment to become more resistant to chemotherapy and that chemotherapeutic metabolism is altered in the face of metastatic disease. We propose a system that will not only provide an all human contextual metastatic micro-environment, but one that is intimately linked to drug metabolism and to normal physiological functions of liver that may hinder or augment the efficacy or toxicities of therapies. More than any other common site of metastasis, the liver experiences dramatic swings in metabolic and hormonal state throughout the day. The extent to which these fluctuations influence malignant behaviors and chemotherapy responses in metastatic tumors is unknown. In this project we capture the complexity of this situation in vitro in a format amenable to incorporation in the drug development pipeline, using a 3D micro- perfused organotypic liver in a multiwell plate format. Our approach is designed to foster development of relatively large, clinically relevant metastatic nodules (>0.5 mm) in functional host liver tissue. We will (i) determine whether cyclic/diurnal changes in hormones, cytokines and nutrients delivered to tumor cells within host liver tissue alters the phenotypic behavior of the tumor cells compared to standard culture, such as proliferation, invasive properties, and expression of specific tumor markers; (ii) Determine whether the efficacy of chemotherapy agents against metastatic tumors is influenced by diurnal control of metabolism and hormones, using a panel of human tumor cells within the liver metastatic microenvironment and both general chemotherapeutics (metabolized and non-metabolized agents) and a targeted bio-therapeutics (in the kinase inhibitor class) and if so, if these are related to properties of the tumor that can be measured in situ (iii) Assess whether the chemotherapeutic toxicities on the liver are altered by metastatic involvement or by cyclical/diurnal variations in the liver affluent (iv) Test the hypothesis that mild inflammatory states of liver stimulate tumor growth and alter efficacy of chemotherapeutics.

描述（由申请人提供）：转移治疗的全人类微物理模型成功根除转移性疾病仍然是降低实体瘤死亡率的巨大挑战。尽管消融方法很少可行，但全身化疗通常是抑制进展和延长生存时间的唯一可行选择，尽管它很少能治愈。我们对化疗药物为何无法消除转移的理解，以及我们创造更有效治疗策略的能力，都受到我们在分子和细胞水平上剖析肿瘤-宿主相互作用的缺陷以及缺乏筛选新疗法的相关模型系统的限制；并且缺乏以相关方式做到这一点的所有人类系统。有证据表明，肿瘤细胞受到转移微环境的影响，对化疗变得更加耐药，并且化疗代谢在面对转移性疾病时发生改变。我们提出了一种系统，不仅提供全人类背景的转移微环境，而且与药物代谢和肝脏正常生理功能密切相关，可能阻碍或增强治疗的功效或毒性。与任何其他常见的转移部位相比，肝脏在一天中的代谢和激素状态会经历剧烈的波动。这些波动在多大程度上影响转移性肿瘤的恶性行为和化疗反应尚不清楚。在这个项目中，我们使用多孔板形式的 3D 微灌注器官型肝脏，以适合纳入药物开发流程的形式在体外捕获这种情况的复杂性。我们的方法旨在促进功能性宿主肝组织中相对较大的、临床相关的转移结节（>0.5 mm）的发展。我们将 (i) 确定与标准培养物相比，输送到宿主肝组织内肿瘤细胞的激素、细胞因子和营养物质的周期性/昼夜变化是否会改变肿瘤细胞的表型行为，例如增殖、侵袭特性和特定肿瘤标志物的表达； (ii) 使用肝转移微环境中的一组人类肿瘤细胞以及一般化疗药物（代谢和非代谢药物）和靶向生物治疗药物（激酶抑制剂类）确定化疗药物对抗转移性肿瘤的功效是否受到代谢和激素的昼夜控制的影响，如果是这样，这些是否与特性相关 (iii) 评估肝脏的化疗毒性是否因转移性受累或肝脏富集物的周期性/昼夜变化而改变 (iv) 检验肝脏的轻度炎症状态刺激肿瘤生长并改变化疗药效的假设。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS).

DOI：
10.1039/c6ib00243a
发表时间：
2017-04-18
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
0
作者：
Maass C;Stokes CL;Griffith LG;Cirit M
通讯作者：
Cirit M

Establishing quasi-steady state operations of microphysiological systems (MPS) using tissue-specific metabolic dependencies.

DOI：
10.1038/s41598-018-25971-y
发表时间：
2018-05-22
期刊：
Scientific reports
影响因子：
4.6
作者：
Maass C;Dallas M;LaBarge ME;Shockley M;Valdez J;Geishecker E;Stokes CL;Griffith LG;Cirit M
通讯作者：
Cirit M

Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System.