3D Engineered Model of Microscopic Colorectal Cancer Liver Metastasis for Adjuvant Chemotherapy Screens

用于辅助化疗筛选的显微结直肠癌肝转移 3D 工程模型

基本信息

批准号：
10556192
负责人：
Shreya Raghavan
金额：
$ 31.67万
依托单位：
TEXAS ENGINEERING EXPERIMENT STATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2028-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556192
关键词：
3-Dimensional Accounting Adjuvant Chemotherapy Adjuvant Therapy Architecture Benchmarking Biocompatible Materials Biological Markers Biomedical Engineering Cancer Patient Cause of Death Cells Cessation of life Chemoresistance Clinic Clinical Clinical Management Clinical Treatment Colorectal Cancer Curative Surgery Detection Disease Disease-Free Survival Disseminated Malignant Neoplasm Drops Elements Engineering Ensure Excision Extracellular Matrix FDA approved Family suidae Future Goals Human Image In Vitro Infiltrative Growth Injections Intestines Libraries Liver Malignant Neoplasms Malignant neoplasm of ovary Metastatic Neoplasm to the Liver Methods Micrometastasis Microscopic Microscopy Modeling Nature Neoplasm Metastasis Oncology Operative Surgical Procedures Outcome Patients Pharmaceutical Preparations Phase I Clinical Trials Positioning Attribute Pre-Clinical Model Recurrence Regenerative Medicine Reproducibility Research Research Support Residual Cancers Residual Neoplasm Rodent Sampling Technology Testing Therapeutic Therapeutic Uses Tissue Engineering Translating Validation Work cancer initiation cancer therapy colon cancer patients colorectal cancer metastasis high risk high-throughput drug screening in vitro Model in vivo Model innovation novel optical imaging patient derived xenograft model patient response patient stratification pre-clinical prevent radiological imaging scaffold screening therapeutic target tumor DNA tumor microenvironment

项目摘要

PROJECT SUMMARY 50% of colorectal cancer (CRC) patients develop liver metastasis (CRLM). Despite adjuvant chemotherapy and surgery, 75% of CRLM recurs due to microscopic residual disease (~1-3mm) that escapes radiographic detection. The objective of this proposal is to engineer and utilize an adjuvant chemotherapy screening platform specific to microscopic CRLM, to identify therapeutics that can eradicate microscopic residual disease. Preclinical models like spheroids and patient-derived xenograft models lack the architecture and extracellular matrix (ECM) composition of the liver metastatic microenvironment. We hypothesize that by engineering the liver metastatic microenvironment, we can produce reproducible instances of microscopic CRLM that can be used for therapeutic screening. Engineered microscopic CRLM models will include: i) decellularized porcine liver biomatrix scaffolds that contain both liver ECM composition and 3D architecture; ii) microscopic spheroids from cells established from patient-derived xenografts of stage IV CRLM. Our methods offer advantages over other decellularized models by: i) using patient-derived cells; and ii) using optical imaging to quantitatively benchmark the establishment of microscopic CRLM; iii) using orthogonal validation including clinical patient-response benchmarking of engineered models to therapeutics; iv) being medium- and high-throughput amenable. The project will build on the PI's (Raghavan) expertise in cancer tissue engineering, but represent significant changes in research directions: The PI's expertise is in studying ovarian cancer initiation and chemoresistance, and this proposal focuses on CRC metastasis and CRLM. To support these research pivots, the PI has assembled an investigative team with expertise in clinical treatment and management of CRC (Kopetz), high-throughput drug screening (Stephan) and microscopy (Walsh). Specific Aims proposed include: (1) : Establish and characterize a bioengineered model of microscopic CRLM from human stage IV CRC; (2) Therapeutic screening of microscopic CRLM using an NCI-approved library; (3) Validation of therapeutic targeting of microscopic CRLM in orthotopic metastasis models. This will be the first instance of a bioengineered in vitro model of microscopic CRLM. Immediate outcomes using the engineered microscopic CRLM model include: i) screening a library of NCI-approved compounds; ii) identifying efficacious strategies to treat microscopic CRLM. Long-term outcomes envisioned include: i) predict the aggressiveness of microscopic residual disease, stratifying patients who are at high-risk of recurrence; ii) testing compounds that can translate into phase I clinical trials in patients with microscopic CRLM identified with circulating tumor DNA biomarkers.

项目摘要 50％的结直肠癌（CRC）患者发生肝转移（CRLM）。尽管佐剂化学疗法和手术，由于微观残留疾病（〜1-3mm）而引起的75％的CRLM复发逃避射线照相检测。该建议的目的是设计和利用辅助针对微观CRLM的化学疗法筛查平台，以识别可以消除微观残留疾病。临床前模型，例如球体和患者衍生的异种移植模型缺乏肝转移的结构和细胞外基质（ECM）组成微环境。我们假设通过设计肝转移微环境，我们可以产生可重现的微观CRLM实例，可用于治疗筛查。工程显微镜CRLM模型将包括：i）脱细胞猪肝Biomatrix支架既包含肝ECM组成和3D体系结构； ii）细胞的微观球体从IV期CRLM的患者衍生异种移植物中建立。我们的方法提供了优势其他脱细胞模型通过：i）使用患者衍生的细胞； ii）使用光学成像定量基准建立微观CRLM； iii）使用正交验证包括临床患者响应基准测试工程模型对治疗剂； iv）存在中等和高通量可正常。该项目将基于PI（Raghavan）的专业知识癌组织工程，但代表研究方向的重大变化：PI的专业知识在研究卵巢癌的启动和化学上，该提议着重于CRC 转移和CRLM。为了支持这些研究枢纽，PI组装了一个调查团队具有CRC（Kopetz）的临床治疗和管理方面的专业知识，高通量药物筛选（Stephan）和显微镜（WALSH）。提出的具体目的包括：（1）：建立和表征来自人类IV CRC的微观CRLM的生物工程模型；（2）治疗使用NCI批准的库筛选微观CRLM；（3）验证治疗靶向原位转移模型中的微观CRLM。这将是一个微观CRLM的体外模型生物工程。使用工程的即时结果微观CRLM模型包括：i）筛选NCI批准化合物的库； ii）识别治疗微观CRLM的有效策略。设想的长期结局包括：i）预测微观残留疾病的侵略性，将处于高风险的患者分层复发； ii）测试化合物，可以转化为I期临床试验的患者微观CRLM鉴定出循环肿瘤DNA生物标志物。