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

• 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
• 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

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）。尽管有佐剂 化疗和手术后，75%的CRLM由于显微镜下残留病变（~1- 3 mm）而复发， 逃过了射线检测。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 根除微观残留疾病。临床前模型，如球状体和患者源性异种移植物 模型缺乏肝转移瘤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， 可以产生可用于治疗筛选的显微CRLM的可再现实例。 工程化的微观CRLM模型将包括：i）脱细胞猪肝生物基质支架 包含肝ECM组合物和3D结构; ii）来自细胞的微观球状体 从IV期CRLM的患者来源的异种移植物建立。我们的方法提供的优势超过 其他脱细胞模型，通过：i）使用患者来源的细胞;和ii）使用光学成像， 定量基准建立微观CRLM; iii）使用正交验证 包括工程模型对治疗的临床患者反应基准; iv） 中等和高通量可接受。该项目将建立在PI（Raghavan）的专业知识基础上， 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，该提案侧重于CRC 转移和CRLM。为了支持这些研究重点，PI组建了一个调查小组， 具有CRC临床治疗和管理的专业知识（Kopetz），高通量药物 筛选（Stephan）和显微镜检查（沃尔什）。具体目标包括：（1）：建立和 表征来自人IV期CRC的微观CRLM的生物工程模型;（2）治疗性 使用NCI-approved文库筛选显微CRLM;（3）验证治疗靶向 原位转移模型中显微镜下CRLM的变化。这将是第一个 显微CRLM的生物工程体外模型。使用设计的 微观CRLM模型包括：i）筛选NCI批准的化合物库; ii）鉴定 治疗显微镜CRLM的有效策略。预期的长期结果包括：i）预测 显微镜下残留疾病的侵袭性，对高风险患者进行分层， ii）测试可以转化为I期临床试验的化合物， 用循环肿瘤DNA生物标志物鉴定的显微镜CRLM。