Expansion of Tumoroid Models for Precise Treatment of the Rectal Cancer Patient

扩大肿瘤模型以精确治疗直肠癌患者

• 批准号: 10576331
• 负责人: Jesse Joshua Smith
• 金额: $ 59.9万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576331
• 关键词: 3-Dimensional; Acceleration; Address; Affect; Anatomy; Bioinformatics; Biology; Biometry; Cancer Patient; Cell Culture Techniques; Cell Line; Chemotherapy and/or radiation; Clinical; Collection; Colorectal Surgery; Communities; Complex; Credentialing; Data; Development; Diagnosis; Disease; Environment; Gene Expression; Genitourinary system; Genomics; Goals; Histology; Human; Implant; Incidence; Individual; Injections; Institution; Invaded; Investigation; KRAS2 gene; Life; Location; Malignant Neoplasms; Memorial Sloan-Kettering Cancer Center; Modeling; Molecular; Mus; Mutation; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Organoids; Pathologic; Pathology; Patient Selection; Patients; Pelvis; Persons; Physiological; Quality of life; Radiation; Radiation Oncology; Radiation therapy; Rectal Adenocarcinoma; Rectal Cancer; Rectum; Research; Resources; Selection for Treatments; Surgical Oncology; TP53 gene; Testing; Transplantation; Tumor Tissue; anticancer research; biobank; cBioPortal; cancer genomics; chemotherapy; clinically relevant; colon cancer cell line; effective therapy; flexibility; implantation; in vivo; in vivo Model; individual patient; individual response; interest; mouse model; patient derived xenograft model; patient response; pilot test; pre-clinical; predicting response; predictive tools; rectal; repository; response; standard care; standard of care; subcutaneous; success; survival outcome; tool; trait; transcriptome; treatment response; tumor; two-dimensional

We propose to develop rectal cancer organoids (tumoroids) as individualized models and to build a large rectal cancer tumoroid repository. Research on rectal cancers is hampered by the paucity of models. Of the few existing in vivo models of rectal cancer, none place the tumors in the rectal lumen, so the models fail to mimic the correct anatomic environment and local invasion. The existing models also have not been observed to metastasize. Another problem is that we lack accurate means to predict whether individual rectal cancer patients will respond to chemotherapy or radiation, both of which are part of the current standard of care. We believe that both the paucity of models and the lack of predictive tools can be addressed by patient-derived tumoroids. Tumoroids can be grown in 3-dimensional culture ex vivo or implanted into mice, so they offer a flexible research platform. In preliminary results, we have derived tumoroid lines from multiple patients' rectal cancers and found them to resemble the corresponding patient tumors. The tumoroids, when implanted in mice endoluminally (i.e. in the rectum), formed locally invasive tumors capable of metastasis. Moreover, we found tumoroids to have clinically relevant responses to chemotherapy and radiation. Thus, drawing from these preliminary data, we hypothesize that rectal cancer tumoroids mirror the traits of their original tumors, can be used to predict patients' response to therapy, and, when implanted endoluminally into mice, can serve as an optimal model of rectal cancer. We plan to develop 100 new tumoroids, which we expect to encompass much of the diversity of human rectal adenocarcinoma. The tumoroids will be analyzed in ex vivo culture and in two mouse models: the endoluminal implantation model and a conventional flank injection model. In these settings, we will test whether the tumoroid accurately reflects its tumor of origin in terms of mutations, histology, and gene expression. We will determine whether response of the tumoroids to patient-specific chemotherapy and radiation can predict the corresponding patient's response. Of particular interest is whether individual human rectal cancers are more accurately modeled by endoluminal implantation than by flank injection. Finally, to integrate our findings into a comprehensive platform for broad use, we will develop a rectal cancer tumoroid biorepository seamlessly integrated with online pathologic, genomic, and model-specific information. The online platform will be built within our institution's cancer genomics portal, then integrated into the NCIP Hub. We have assembled a collaborative team with expertise in colorectal surgical oncology, radiation oncology, and pathology; organoids; mouse models; biostatistics; and bioinformatics. We anticipate that the proposed research will credential tumoroids as accurate models for rectal cancer research and for predicting patient responses to therapy. The large tumoroid biorepository is likely to stimulate research on new treatments for rectal cancer. The ultimate result will be new treatment options and better treatment selection for patients affected by this deadly disease.

我们建议开发直肠癌类器官（类肿瘤）， 个体化模型和建立大型直肠癌类瘤库。直肠癌的研究是 由于缺乏模型而受到阻碍。在现有的几种直肠癌体内模型中，没有一种将肿瘤 在直肠腔内，因此模型不能模拟正确的解剖环境和局部侵犯。的 也没有观察到现有模型转移。另一个问题是我们缺乏准确的手段 预测个体直肠癌患者是否会对化疗或放疗产生反应，这两种方法都是 目前的护理标准。我们认为，缺乏模型和预测工具 可以通过患者源性类肿瘤来解决。类肿瘤可以在离体或体外三维培养物中生长。 植入小鼠体内，因此它们提供了一个灵活的研究平台。在初步结果中，我们已经衍生出了类肿瘤 从多个患者的直肠癌中提取的线，发现它们类似于相应的患者肿瘤。的 当将类肿瘤植入小鼠的腔内（即直肠）时，形成局部侵袭性肿瘤， 转移此外，我们发现类肿瘤对化疗有临床相关的反应， 辐射因此，根据这些初步数据，我们假设直肠癌类瘤反映了 它们原始肿瘤的特征，可用于预测患者对治疗的反应， 在小鼠体内进行，可以作为直肠癌的最佳模型。 我们计划开发100个新的类肿瘤，我们希望它能涵盖人类直肠癌的大部分多样性。 腺癌将在离体培养物和两种小鼠模型中分析类肿瘤： 注入模型和常规侧面注入模型。在这些设置中，我们将测试 类肿瘤在突变、组织学和基因表达方面准确地反映了其肿瘤起源。我们将 确定类肿瘤对患者特异性化疗和放疗的反应是否可以预测 患者的相应反应。特别令人感兴趣的是，个体人类直肠癌是否更多地 通过腔内植入比通过侧腹注射更准确地建模。最后，将我们的发现整合到一个 广泛使用的综合平台，我们将无缝开发直肠癌类肿瘤生物储存库 与在线病理学、基因组学和模型特异性信息相结合。将搭建线上平台 在我们机构的癌症基因组学门户网站，然后集成到NCIP中心。我们组建了一个 具有结直肠外科肿瘤学、放射肿瘤学和病理学专业知识的协作团队;类器官; 小鼠模型;生物统计学;和生物信息学。我们预计，拟议中的研究将证明 类肿瘤作为直肠癌研究和预测患者对治疗反应的精确模型。的 大型类肿瘤生物储存库可能会刺激直肠癌新疗法的研究。最终 结果将是新的治疗选择和更好的治疗选择受这种致命疾病影响的患者。