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.

项目概要 50% 的结直肠癌 (CRC) 患者出现肝转移 (CRLM)。尽管有佐剂化疗和手术后，75% 的 CRLM 因显微镜下残留病灶（~1-3mm）而复发，逃脱射线照相检测。该提案的目的是设计和利用佐剂针对显微 CRLM 的化疗筛选平台，以确定可以的治疗方法根除微小残留病灶。临床前模型，如球体和患者来源的异种移植物模型缺乏肝转移的结构和细胞外基质 (ECM) 组成微环境。我们假设通过改造肝转移微环境，我们可以产生可重复的显微 CRLM 实例，可用于治疗筛选。工程显微 CRLM 模型将包括： i) 脱细胞猪肝脏生物基质支架包含肝脏 ECM 成分和 3D 架构； ii) 细胞的微观球体由 IV 期 CRLM 患者来源的异种移植物建立。我们的方法比以下方法具有优势其他脱细胞模型：i) 使用患者来源的细胞； ii) 使用光学成像定量标杆微观CRLM的建立； iii) 使用正交验证包括治疗工程模型的临床患者反应基准； iv) 存在适合中、高通量。该项目将建立在 PI (Raghavan) 的专业知识之上癌症组织工程，但代表了研究方向的重大变化：PI的专业知识正在研究卵巢癌的发生和化疗耐药性，该提案重点关注结直肠癌转移和 CRLM。为了支持这些研究重点，PI 组建了一个调查小组拥有CRC临床治疗和管理方面的专业知识（Kopetz），高通量药物筛选（Stephan）和显微镜检查（Walsh）。提出的具体目标包括： (1)：建立和表征人类 IV 期 CRC 的微观 CRLM 生物工程模型； (2) 治疗性使用 NCI 批准的文库筛选显微 CRLM； (3) 治疗靶向的验证原位转移模型中的显微 CRLM 的研究。这将是第一个实例显微 CRLM 的生物工程体外模型。使用工程设计立即产生结果微观 CRLM 模型包括： i) 筛选 NCI 批准的化合物库； ii) 识别治疗微观 CRLM 的有效策略。预期的长期结果包括： i) 预测微观残留病灶的侵袭性，对高危人群进行分层复发； ii) 测试可转化为 I 期临床试验的化合物显微 CRLM 与循环肿瘤 DNA 生物标志物进行鉴定。