Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Res. 2022 Jun 15;82(12):2298-2312. doi: 10.1158/0008-5472.CAN-21-4128.
Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here, we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDO) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically expanded Lgr5+ intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination-mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses.
Analysis of inherent tissue radiosensitivity of patient-derived organoids may provide a readout predictive of neoadjuvant therapy response to radiation in rectal cancer, potentially allowing pretreatment stratification of patients likely to benefit from this approach.
在手术前确定对化疗或放化疗有反应的结直肠癌患者群体仍然是一个挑战。最近，经过验证的用于类器官照射的小鼠方案采用了单击中靶多靶（SHMT）算法，该算法产生一个单一值 D0，作为固有组织放射敏感性的度量。在这里，我们将这些方案转化为人体组织，以评估源自接受新辅助治疗的患者的正常人类肠道和直肠肿瘤的患者衍生类器官（PDO）的放射反应性。虽然具有对数扩增 Lgr5+肠干细胞群的腺瘤来源的 PDO 保留了正常结直肠 PDO 的放射抗性表型，但恶性转化导致来自大量患者亚群的 PDO 由于同源重组介导的 DNA 修复减少而显示出明显的放射敏感性。一项原理验证性的临床试验表明，直肠癌患者对新辅助放化疗的反应，包括完全缓解，与他们的 PDO D0 值密切相关。总体而言，在转化为结直肠腺癌后，大量患者会出现广泛的辐射敏感性，可通过 PDO 辐射反应的 SHMT 分析来识别。
分析患者衍生类器官的固有组织放射敏感性可能为直肠癌对放射治疗的新辅助治疗反应提供预测指标，有可能在治疗前对可能受益于这种方法的患者进行分层。
