Patient-derived organoids reveal rectal cancers develop radiosensitivity

患者来源的类器官揭示直肠癌产生放射敏感性

基本信息

批准号：
10343663
负责人：
Richard N Kolesnick
金额：
$ 24.33万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-05 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343663
关键词：
Ablation Adenocarcinoma Affect BRCA1 gene Cancer cell line Carcinoma Cell Culture Techniques Clinical Colon Colon Carcinoma Colonic Adenoma Colorectal Colorectal Adenocarcinoma Colorectal Cancer Colorectal Neoplasms Copy Number Polymorphism DNA DNA Damage DNA Repair DNA Repair Gene DNA Sequence Alteration DNA-PKcs Data Disease-Free Survival Epigenetic Process Epithelial Evolution Funding Agency Genes Genetic Genomic DNA Goals Growth Human In complete remission Institutional Review Boards Malignant Neoplasms Measures Modeling Molecular Mucous Membrane Mutation Mutation Spectra Neoadjuvant Therapy Nonhomologous DNA End Joining Normal tissue morphology Organ Organoids Patients Phenotype Primary Carcinoma Protocols documentation Radiation Radiation Dose Unit Radiation Tolerance Radiation therapy Rectal Cancer Rectal Neoplasms Relapse Research Resistance Resolution Structural defect Technology The Cancer Genome Atlas Time Tissue Harvesting Tissues Tumor Tissue XRCC4 gene Xenograft procedure adenoma chemoradiation colon cancer patients colorectal cancer progression exome gene repair high risk homologous recombination improved individual patient patient response patient subsets personalized intervention preclinical study radiation resistance radiation response radioresistant repaired response standard of care success transcriptome sequencing transcriptomics treatment response tumor tumor progression

项目摘要

The Fearon and Vogelstein multistep cancer progression model of colon cancer defines key genetic changes associated with progression from normal colorectal tissue to early/late adenoma, primary carcinoma and metastatic dissemination. Extensive research has defined genetic/epigenetic alterations that drive colorectal cancer progression. However, systematic stage-by-stage assessment of genetic changes associated with colorectal tumor response is limited. Recent emergence of organoid technology has bridged the gap between cancer cell lines and xenografts, and advanced the ability to explore therapeutic responses of tumors cultured ex vivo as organoids derived from freshly- isolated tumor tissue. Furthermore, such patient-derived organoids (PDOs) recapitulate the mutational spectra in colorectal cancer. Here we will employ this technology to characterize the radiation responses of multi-stage colorectal cancer. Our biospecimen protocol (IRB-15-191) to harvest tissue from primary human colorectal cancer and normal colorectal mucosal epithelium pre- and post-neoadjuvant chemoradiotherapy and to grow/study PDOs therefrom has revealed 2 findings: 1) While normal colon and adenoma PDOs are radioresistant, surprisingly adenocarcinoma PDOs are as much as 1-log radiosensitive; and 2) Selection post neo-adjuvant therapy reveals loss of radiosensitivity. To our knowledge, these are the first data demonstrating that colorectal cancers develop inherent radiosensitivity when progressing from normal tissue and adenoma into adenocarcinoma. The goals of this study are: 1) To determine using foci technology the dysfunctional DNA repair mechanism (HR, NHEJ or both) that leads to human colorectal cancer radiosensitivity and to identify its molecular basis and 2) To determine whether the most radiosensitive cancers yield complete response after neo-adjuvant therapy.

vareon和Vogelstein多步癌的结肠癌的进展模型定义了关键遗传与从正常结直肠组织到早期/晚期腺瘤相关的变化，主要癌和转移性传播。广泛的研究定义了遗传/表观遗传学驱动大肠癌进展的改变。但是，逐个阶段的系统评估与结直肠肿瘤反应相关的遗传变化受到限制。最近的出现器官技术已经弥合了癌细胞系和异种移植物之间的差距，并提出了能够探索过体内培养的肿瘤的治疗反应，因为源自新鲜的器官分离的肿瘤组织。此外，这种患者衍生的类器官（PDOS）概括了结直肠癌的突变光谱。在这里，我们将采用这项技术来表征多阶段大肠癌的辐射反应。我们的生物测量协议（IRB-15-191）从原发性人类结肠癌和正常结直肠粘膜上皮的收获组织并从中添加/研究pdos的核辅助化学疗法和研究pdos揭示了2个发现： 1）虽然正常结肠和腺瘤PDO是放射耐药的，但令人惊讶的是腺癌PDOS是多达1-log放射素敏感； 2）新辅助治疗后的选择揭示了放射敏性。据我们所知，这些是第一个数据，证明了结直肠癌从正常组织和腺瘤发展到腺癌。这项研究的目标是：1）确定使用焦点技术功能失调 DNA修复机制（HR，NHEJ或两者），导致人类结直肠癌放射敏性和确定其分子基础和2）确定最放射敏感的癌症是否产生新辅助治疗后完全反应。