Engineering personalized micro-tumor ecosystems

设计个性化微肿瘤生态系统

• 批准号: 10261573
• 负责人: Ali Khademhosseini
• 金额: $ 61.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261573
• 关键词: 3-Dimensional; Accounting; Achievement; Address; Algorithms; Antibiotics; Antineoplastic Agents; Area; Autologous; Biocompatible Materials; Biological; Biological Assay; Biological Markers; Biomimetics; Biopsy; Bioreactors; Cancer Patient; Cause of Death; Cessation of life; Cetuximab; Characteristics; Clinical; Clinical Data; Colorectal Cancer; Complex; Consensus; Data; Development; Drug Combinations; Ecosystem; Engineering; Future; Glucose; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Hydrogels; In Vitro; Individual; KRAS2 gene; Lab-On-A-Chips; Liquid substance; Malignant Neoplasms; Metabolic; Microfluidics; Miniaturization; Modeling; Molecular Profiling; Nature; Needle biopsy procedure; Neoadjuvant Therapy; Outcome; Parents; Pathologic; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Prediction of Response to Therapy; Proteins; Publishing; Quality of life; Regimen; Rest; Screening for cancer; Serum; Specificity; Supplementation; System; Testing; Therapeutic; Therapeutic Agents; Training; Translating; Treatment Cost; Treatment Protocols; Tumor Tissue; Tumor stage; Tumor-Derived; United States; Variant; Work; Xenograft Model; base; cancer therapy; chemotherapy; cytokine; design; effective therapy; fluid flow; genetic profiling; genetic testing; humanized mouse; improved; in vivo; large scale data; machine learning algorithm; malignant breast neoplasm; miniaturize; novel; outcome prediction; patient response; personalized medicine; personalized screening; precision medicine; prevent; response; side effect; survival outcome; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor microenvironment; tumor xenograft

Abstract Cancer is one of the leading causes of death in the United States, accounting for near 1 in every 4 deaths. However, despite the recent development of subtype-specific personalized therapy based on achievements in the fields of molecular and genetic profiling, many cancer treatments still have low efficacy which mostly arise from the limited ability to predict the patient tumor responses to therapeutic agents. The major reason that current therapeutics often cannot translate into a successful clinical outcomes is because of the complex tumor microenvironment and heterogeneity that limit the predictive power of the biomarker-guided strategies for chemotherapy. Therefore, the successful engineering of personalized three-dimensional (3D) tumor ecosystem that can recapitulate the tumor microenvironment and heterogeneity in vitro is strongly desired to accurately predict patients’ responses to anti-cancer drugs and thus further improve patient outcome. Here we propose to develop a personalized breast-cancer-ecosystem-on-a-chip platform for personalized screening of cancer chemotherapeutics with high accuracy by utilizing patient-derived tumor explant, defined tumor grade-matched biomaterial matrices and autologous patient serum to mimic patient-specific tumor hallmarks. The proposed cancer-ecosystem-on-a-chip will also be tightly regulated under physiological fluid dynamics. In this project, we have hypothesized that 1) the use of tumor explant will embrace the critical components of the tumor heterogeneity of the patient, 2) the combination of defined tumor grade-matched matrix, autologous patient serum, and a microfluidic bioreactor will prevent the phenotype alteration of the tumor explant, and 3) the integration of a machine-learning algorithm with the cancer-ecosystem-on-a-chip platform will provide more accurate, unbiased prediction of the patient responses to chemotherapeutics based on the data gathered from the engineered tumor model. Our preliminary results show that the combination of tumor explant culture and tumor-derived matrix constituents had predicted therapeutic responses with 100% sensitivity. Our preliminary results show high specificity throughout a range of cancers including breast cancer, colorectal cancer, and head and neck squamous cell carcinoma, and thus the findings can have broad applications, and can emerge as a paradigm shift in the management of cancer.

抽象的 癌症是美国死亡的主要原因之一，每4人死亡约为1个。 然而，尽管最近发展了基于亚型特定于亚型的个性化疗法 分子和基因分析领域，许多癌症治疗仍然具有低效率，主要出现 从预测患者肿瘤对治疗剂反应的能力有限。当前的主要原因 治疗剂通常无法转化为成功的临床结果，这是因为复杂的肿瘤 微环境和异质性限制了生物标志物引导策略的预测能力 化学疗法。因此，个性化的三维（3D）肿瘤生态系统的成功工程 可以在体外概括肿瘤微环境和异质性，以准确地需要 预测患者对抗癌药物的反应，从而进一步改善患者预后。在这里我们建议 开发一个个性化的乳腺癌生态系统，以启用癌症的个性化筛查 通过使用患者衍生的肿瘤外植体，定义的肿瘤匹配，具有高精度的化学治疗药 生物材料材料和自体患者血清与模拟患者特异性肿瘤标志。提议 片上的癌症生态系统也将在物理流体动力学下受到严格调节。在这个项目中，我们 假设1）使用肿瘤外植体将包含肿瘤的关键成分 患者的异质性，2）定义的肿瘤匹配矩阵，自体患者的组合 血清和微流体生物反应器将防止肿瘤外植体的表型改变，3） 将机器学习算法与芯片上的癌症生态系统的集成将提供更多 基于从中收集的数据，对患者对化学治疗剂的反应的准确，公正的预测 工程肿瘤模型。我们的初步结果表明，肿瘤外植体培养和 肿瘤来源的基质组成预测了100％敏感性的治疗反应。我们的初步 结果显示在整个癌症中都表现出很高的特异性，包括乳腺癌，有色癌和头部 和颈部鳞状细胞癌，因此这些发现可以具有广泛的应用，并且可以作为一个 癌症管理的范式转移。

项目成果

Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer.

• DOI: 10.1158/0008-5472.can-19-4036
• 发表时间: 2020-12-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Smalley M;Natarajan SK;Mondal J;Best D;Goldman D;Shanthappa B;Pellowe M;Dash C;Saha T;Khiste S;Ramadurai N;Eton EO;Smalley JL;Brown A;Thayakumar A;Rahman M;Arai K;Kohandel M;Sengupta S;Goldman A
• 通讯作者: Goldman A

Cancer-on-a-Chip for Modeling Immune Checkpoint Inhibitor and Tumor Interactions.

• DOI: 10.1002/smll.202004282
• 发表时间: 2021-03
• 期刊: Small (Weinheim an der Bergstrasse, Germany)
• 作者: Jiang X;Ren L;Tebon P;Wang C;Zhou X;Qu M;Zhu J;Ling H;Zhang S;Xue Y;Wu Q;Bandaru P;Lee J;Kim HJ;Ahadian S;Ashammakhi N;Dokmeci MR;Wu J;Gu Z;Sun W;Khademhosseini A
• 通讯作者: Khademhosseini A