Thng Dexter Kai Hao, Hooi Lissa, Siew Bei En, Lee Kai-Yin, Tan Ian Jse-Wei, Lieske Bettina, Lin Norman Sihan, Kow Alfred Wei Chieh, Wang Shi, Rashid Masturah Bte Mohd Abdul, Ang Chermaine, Koh Jasmin Jia Min, Toh Tan Boon, Tan Ker-Kan, Chow Edward Kai-Hua
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
NPJ Precis Oncol. 2024 Feb 27;8(1):52. doi: 10.1038/s41698-024-00543-8.
Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC.
在全球范围内，结直肠癌（CRC）是第三大常见癌症。进展为晚期转移性恶性肿瘤（转移性结直肠癌，metCRC）通常预示着预后不良，因为患者的5年生存率会迅速下降。尽管有许多用于治疗metCRC的全身疗法，但由于肿瘤内和肿瘤间的异质性导致治疗耐药性的出现，这些方案的长期疗效常常受到阻碍。此外，并非所有全身疗法都有可准确预测患者反应的相关生物标志物。因此，功能个性化肿瘤学（FPO）方法能够识别患者特异性的组合脆弱性和协同组合，作为有效的治疗策略。为此，我们建立了一组源自结直肠癌患者的类器官（PDO）作为临床相关生物系统，其中三对匹配的转移性结直肠癌PDO分别来自原发部位（原发性结直肠癌，ptCRC）和转移病灶（转移性结直肠癌，mCRC）。对这些PDO进行的组织学和基因组特征分析表明，它们保留了亲代肿瘤中的组织病理学和遗传特征。随后在这些PDO对中应用表型分析药物组合询问平台——二次表型优化平台，确定了患者对基于表观遗传学的联合疗法的特异性药物敏感性谱。最值得注意的是，来自一名患者的匹配PDO尽管基因相似，但对合理设计的药物组合表现出不同的敏感性模式。这些发现共同凸显了当前基因组驱动的精准医学在指导metCRC患者治疗策略方面的局限性。相反，这表明表观基因组分析和FPO的应用可以补充对新型组合脆弱性的识别，以靶向同步的ptCRC和mCRC。
