Establishing efficient technologies for ovarian cancer organoid derivation from fresh tumor resections

建立从新鲜肿瘤切除物中衍生卵巢癌类器官的有效技术

• 批准号: 10218117
• 负责人: Laura Andres-Martin
• 金额: $ 19.58万
• 依托单位: NEW YORK STEM CELL FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218117
• 关键词: 3-Dimensional; Accounting; Adoption; Affect; Antineoplastic Agents; Automation; Basic Science; Biological Assay; Biological Models; Cancer Etiology; Cancer Patient; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Clinical; Clinical Research; Colorectal Cancer; Communities; Cryopreservation; Dependence; Derivation procedure; Development; Disease; Drops; Drug resistance; Ensure; Evolution; Excision; Exhibits; Experimental Models; Formulation; Frequencies; Future; Generations; Genetic; Genetic Transcription; Genomics; Genotype; Goals; Growth; Growth Factor; Heterogeneity; Histologic; Histology; In Vitro; Laboratory Research; Liquid substance; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Memorial Sloan-Kettering Cancer Center; Methods; Modeling; Molecular; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; Organoids; Ovarian Carcinoma; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Pre-Clinical Model; Process; Protocols documentation; Research; Robotics; Sampling; Standardization; Stem Cell Development; Survival Rate; Suspensions; Technology; Testing; Therapeutic; TimeLine; Tissues; Translating; Treatment Efficacy; Treatment outcome; Tumor-Derived; Woman; Work; adult stem cell; anticancer research; base; biobank; cancer cell; cancer type; chemotherapeutic agent; chemotherapy; clinical subtypes; clinically relevant; design; drug sensitivity; experimental study; genetic information; high throughput screening; high-throughput drug screening; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; malignant breast neoplasm; matrigel; neoplastic cell; ovarian neoplasm; pancreatic cancer patients; patient response; personalized medicine; preservation; relapse patients; response; standard of care; stem cells; success; tissue culture; tumor; tumor heterogeneity

PROJECT SUMMARY Ovarian cancer is among the deadliest cancer types, with a 5-year survival rate of only 47%. Survival rates for women with ovarian cancer have not changed in the past 25 years. This is partly due to the high frequency of patient relapses (over 75%) with cancers exhibiting drug resistance, making these cancers extremely difficult to treat effectively. Exacerbating the issue is that ovarian carcinomas are especially heterogeneous with respect to the cell of origin, genetics, and clinical evolution. These are major impediments to establishing effective experimental models for laboratory research, which are critical to improve the understanding and treatment of each patient's disease. Recent technological advances have enabled the development of `organoids' – 3D self-organized tissue cultures – from adult stem cells and subsequently from tumor samples. Tumor-derived organoids are arranged in a way that mimics the original tumor organization. Tumor-derived organoids that can be cultured long-term offer the advantage of extending the experimental lifetime of tumor resection samples, which are currently a limiting step in cancer research. Recent studies have shown that these organoids faithfully recapitulate the genetics, histology, and drug responses of original tumor samples from breast, colorectal, and pancreatic cancer patients, paving the way for `living biobanks' of these cancer types. Ovarian cancer organoids have been more challenging to establish, partly because of their heterogeneity and unique growth requirements – but preliminary successes have now made it feasible to develop technology for ovarian cancer organoid derivation from fresh tumor samples. This project aims to build on these recent advances in the development of stem cell culture and stem-cell-based organoids to establish platform technology for ovarian cancer organoid generation. Numerous media conditions will be tested, which in a proof of concept will incorporate tumor genetic information to define specific growth requirements. The organoid models generated will be validated to ensure concordance with the original tumor genetics and histology, modifying the protocols accordingly. This project presents a unique opportunity to investigate whether organoid drug sensitivities correspond to patient treatment outcomes, as patients will be treated with standard-of-care chemotherapies following surgery to take the tumor samples, and organoids will be tested with the same agents. Finally, the protocols generated will be adapted for robotic automation so that numerous samples can be processed and biobanked in parallel at large scale, facilitating future adoption of these methods in a clinical setting. Taken together, this project will establish a new patient-specific preclinical model system to accelerate basic and clinical ovarian cancer research, ranging from disease mechanisms to personalized medicine approaches that will help to prioritize the treatments most likely to be effective for each patient.

项目摘要 卵巢癌是最致命的癌症类型之一，5年的存活率仅为47％。生存率 在过去的25年中，卵巢癌的妇女没有改变。这部分是由于高频 患者继电器（超过75％）具有表现出耐药性的癌症，使这些癌症极为困难 有效治疗。加剧了这个问题是卵巢癌特别异质 尊重来源，遗传学和临床进化的细胞。这些是建立的主要障碍 实验室研究的有效实验模型，这对于改善理解和 治疗每个患者疾病。最近的技术进步使得 `类器官 - 3D自组织的组织培养物 - 来自成年干细胞，随后来自肿瘤样品。 肿瘤衍生的类器官以模仿原始肿瘤组织的方式排列。肿瘤来源 可以长期培养的类器官提供了延长实验寿命的优势 肿瘤切除样品，目前是癌症研究中的限制步骤。最近的研究 表明这些器官忠实地概括了原始的遗传学，组织学和药物反应 乳腺癌，结直肠癌和胰腺癌患者的肿瘤样品为“活生物库”铺平了道路 这些癌症类型。卵巢癌的类器官的建立更具挑战性，部分原因是 他们的异质性和独特的增长要求 - 但初步的成功现在使其可行 从新鲜的肿瘤样品开发了卵巢癌器官衍生的技术。这个项目旨在 基于这些最新的干细胞培养和基于干细胞的器官的进步 建立卵巢癌器官产生的平台技术。许多媒体条件 将进行测试，这将在概念证明中结合肿瘤遗传信息以定义特定的生长 要求。生成的器官模型将得到验证，以确保与原始肿瘤一致 遗传学和组织学，对方案进行相应的修改。该项目为一个独特的机会提供了 研究器官药物敏感性是否对应于患者的治疗结果，因为患者将是 手术后用护理标准化学疗法治疗肿瘤样品和类器官 将与同一代理进行测试。最后，生成的协议将用于机器人自动化，因此 可以在大规模上并行处理和生物群，以支持将来的采用 这些方法在临床环境中。综上所述，该项目将建立一个新的患者特定于患者 临床前模型系统，以加速基本和临床卵巢癌研究 个性化医学方法的疾病机制将有助于优先考虑治疗 最有可能对每个患者有效。