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

项目总结 卵巢癌是最致命的癌症类型之一，5年存活率只有47%。存活率 在过去的25年里，患有卵巢癌的女性没有改变。这在一定程度上是由于 患者复发(超过75%)的癌症表现出耐药性，使这些癌症变得极其困难 有效地治疗。使这一问题雪上加霜的是，卵巢癌与 关于细胞起源、遗传学和临床进化的。这些都是建立 实验室研究的有效实验模型，这对于提高理解和 治疗每一位病人的疾病。最近的技术进步使 “类器官”--3D自组织组织培养--来自成人干细胞，随后来自肿瘤样本。 肿瘤衍生的有机化合物以模仿原始肿瘤组织的方式排列。肿瘤来源 可长期培养的有机化合物具有延长实验寿命的优点 肿瘤切除样本，这是目前癌症研究中的一个限制步骤。最近的研究表明 表明这些有机化合物忠实地概括了原始的遗传学、组织学和药物反应。 来自乳腺癌、结直肠癌和胰腺癌患者的肿瘤样本，为建立生物信息库铺平了道路 这些癌症类型。卵巢癌有机化合物的建立更具挑战性，部分原因是 它们的异质性和独特的增长要求-但初步的成功现在使其成为可能 开发从新鲜肿瘤样本中提取卵巢癌有机化合物的技术。该项目旨在 建立在干细胞培养和干细胞类有机物发展的这些最新进展的基础上 建立卵巢癌类有机物生成的平台技术。众多媒体条件 将进行测试，在概念验证中将结合肿瘤遗传信息来定义特定的生长 要求。生成的器官模型将得到验证，以确保与原始肿瘤的一致性 遗传学和组织学，相应地修改方案。这个项目提供了一个独特的机会来 调查有机类药物敏感性是否与患者的治疗结果相对应，患者将会这样做 在手术后接受标准护理化疗以获取肿瘤样本和有机化合物 将用相同的试剂进行测试。最后，生成的协议将适用于机器人自动化，因此 大量样本可以大规模地并行处理和生物库，促进未来的采用 这些方法在临床环境中的应用。综上所述，该项目将建立一个新的针对患者的 加快基础和临床卵巢癌研究的临床前模型系统，范围从 疾病机制到个性化的医学方法，这将有助于确定治疗的优先顺序 最有可能对每个病人有效。

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.