Harnessing human brain and liver microphysiological systems for testing therapeutics for metastatic melanoma

利用人脑和肝脏微生理系统测试转移性黑色素瘤的治疗方法

基本信息

批准号：
10462511
负责人：
WILLIAM L. MURPHY
金额：
$ 149.23万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462511
关键词：
3-Dimensional Address Adoption Affect Animals Antineoplastic Agents Biological Assay Biological Models Brain Cancer Patient Cell Proliferation Cells Clinic Clinical Clinical Research Clinical Trials Collaborations Cutaneous Melanoma Devices Distant Drug Interactions Drug Targeting Drug usage Engineering Ensure Environment Extravasation Foundations Funding Genotype Growth Human Immune Implant In Vitro Institution Laboratories Liver Measures Medical center Melanoma Cell Metastatic Melanoma Modeling Mus National Center for Advancing Translational Sciences Nature Neoplasm Metastasis Organ Organoids Outcome Patient Selection Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Physicians Plants Primary Neoplasm Process Protocols documentation Research Research Project Grants Sampling Savings Seeds Site Soil Source Standardization Testing Tissue Microarray Tissues Translating Translations Tumor Bank Tweens Universities Uveal Melanoma Wisconsin base cancer cell cancer therapy cell type data modeling design drug efficacy drug response prediction effectiveness evaluation genotyped patients human model human stem cells improved induced pluripotent stem cell interest melanoma microphysiology system neoplastic cell neurovascular unit novel therapeutics optimal treatments organ on a chip patient derived xenograft model patient response precision medicine predicting response response targeted treatment therapeutic evaluation treatment response tumor tumor growth working group

项目摘要

Project Summary The standard for assessing the effectiveness of drugs to treat metastatic melanoma is the patient's response, but there is a pressing clinical need for a human surrogate model that could support prediction of drug efficacy, thereby saving the patient from trial and error treatments, and that would ultimately serve as a guide for the selection of patient-targeted drug therapies. Today, there is significant interest in the use of patient-derived xenografts (PDXs), in which a patient's tumor is implanted into an immune-deficient mouse, to create in the mouse a model of the patient's tumor. Unfortunately, this process is slow and expensive and is based upon an animal microenvironment rather than a human one. Microphysiological systems (MPS), which encompass organs-on-chips, tissue chips, and engineered organoids, can be constructed using human cells to create an in vitro microenvironment. The proposed research would build upon a strong collaboration at Vanderbilt University, the University of Pittsburgh, and the University of Wisconsin to develop powerful MPS to address the need for models of a patient's response to cancer therapy. This project will study how the tissue microenvironment affects the growth of metastatic melanoma cells and their response to drugs by using the Vanderbilt neurovascular unit tissue chip, the Pittsburgh liver-on-chip, and the Wisconsin engineered organoids for brain and liver, each of which includes multiple cell types. The research will focus on the final stage in the metastatic cascade – the growth of tumor cells at sites distant from the primary tumor. This growth is governed by “seed and soil” interaction between the tumor “seed” and the tissue microenvironment “soil.” Instead of using a mouse as the soil, patients' cancer cells will be planted into the soil provided by brain and liver MPS constructs derived from human induced pluripotent stem cells. The aims are 1) Implement a common set of human organ constructs (liver-on-chip, neurovascular unit, and engineered organoid from a single human stem cell source), 2) Demonstrate successful seeding of these human organ constructs with metastatic cutaneous melanoma or uveal melanoma cells derived from Vanderbilt and Pittsburgh patients, and 3) Compare the response to drugs by patients' cancer cells that have been seeded into the organs-on-chips and engineered organoids with the response to the same drugs by existing PDX lines. This project will provide guidance as to which in vitro human model might be more predictive of patient outcome when translated to the clinic, based in part upon the type of tumor, the nature of the patient sample, and the patient genotype. It will also test the hypothesis that the human MPS devices and models developed at Vanderbilt, Pittsburgh, and Wisconsin will provide a more realistic, in vitro, three-dimensional human microenvironment to study tumor metastasis than mouse PDXs. The final phase will be a proof-of-concept demonstration of precision medicine in which the microenvironment of the brain and liver could be from the patient's induced pluripotent stem cells.

项目概要评估药物治疗转移性黑色素瘤有效性的标准是患者的反应，但临床迫切需要一种可以支持药物疗效预测的人类替代模型，将患者从反复试验的治疗中拯救出来，这最终将成为治疗的指南如今，人们对使用源自患者的药物疗法产生了浓厚的兴趣。异种移植（PDX），将患者的肿瘤植入免疫缺陷小鼠体内，以在不幸的是，这个过程缓慢且昂贵，并且是基于一个模型。动物微环境而不是人类微生理系统（MPS），其中包括。器官芯片、组织芯片和工程类器官可以使用人体细胞构建拟议的研究将建立在范德比尔特大学的强有力合作的基础上。大学、匹兹堡大学和威斯康星大学将开发强大的 MPS 来解决需要建立患者对癌症治疗反应的模型，该项目将研究组织如何变化。微环境通过使用微环境影响转移性黑色素瘤细胞的生长及其对药物的反应范德比尔特神经血管单元组织芯片、匹兹堡肝脏芯片和威斯康星州工程类器官对于大脑和肝脏，每个细胞都包含多种细胞类型，该研究将集中在最后阶段。转移级联反应——肿瘤细胞在远离原发肿瘤的部位生长。这种生长受到控制。肿瘤“种子”与组织微环境“土壤”之间的“种子和土壤”相互作用。以小鼠为土壤，将患者的癌细胞种植到大脑和肝脏MPS提供的土壤中源自人类诱导多能干细胞的构建体的目的是 1) 实现一组通用的。人体器官构建体（芯片上的肝脏、神经血管单元和来自单个人体干细胞的工程类器官细胞来源），2）证明这些人体器官构建体与转移性皮肤成功播种来自范德比尔特和匹兹堡患者的黑色素瘤或葡萄膜黑色素瘤细胞，以及 3) 比较植入器官芯片并经过改造的患者癌细胞对药物的反应现有 PDX 系对相同药物有反应的类器官该项目将提供指导。当转化为临床时，哪种体外人体模型可能更能预测患者的结果，基于部分取决于肿瘤的类型、患者样本的性质以及患者的基因型。它还将测试。假设范德比尔特、匹兹堡和威斯康星州开发的人类 MPS 设备和模型将提供比传统技术更真实的体外三维人体微环境来研究肿瘤转移最后阶段将是精准医学的概念验证演示，其中大脑和肝脏的微环境可能来自患者的诱导多能干细胞。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modeling the Effect of the Metastatic Microenvironment on Phenotypes Conferred by Estrogen Receptor Mutations Using a Human Liver Microphysiological System.

使用人类肝脏微生理系统模拟转移微环境对雌激素受体突变所赋予表型的影响。

DOI：
发表时间：
2019
期刊：
影响因子：
4.6
作者：
Miedel, Mark T;Gavlock, Dillon C;Jia, Shanhang;Gough, Albert;Taylor, D Lansing;Stern, Andrew M
通讯作者：
Stern, Andrew M

A protocol for rapid pericyte differentiation of human induced pluripotent stem cells.

人类诱导多能干细胞快速周细胞分化的方案。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Aisenbrey, Elizabeth A;Torr, Elizabeth;Johnson, Hunter;Soref, Cheryl;Daly, William;Murphy, William L
通讯作者：
Murphy, William L