PDF(Pubmed)
Abstract：
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Therefore, the need for new therapeutic strategies is still a challenge. Surgery and chemotherapy represent the first-line interventions; nevertheless, the prognosis for metastatic CRC (mCRC) patients remains unacceptable. An important step towards targeted therapy came from the inhibition of the epidermal growth factor receptor (EGFR) pathway, by the anti-EGFR antibody, Cetuximab, or by specific tyrosine kinase inhibitors (TKI). Cetuximab, a mouse-human chimeric monoclonal antibody (mAb), binds to the extracellular domain of EGFR thus impairing EGFR-mediated signaling and reducing cell proliferation. TKI can affect the EGFR biochemical pathway at different steps along the signaling cascade. Apart from Cetuximab, other anti-EGFR mAbs have been developed, such as Panitumumab. Both antibodies have been approved for the treatment of KRAS-NRAS wild type mCRC, alone or in combination with chemotherapy. These antibodies display strong differences in activating the host immune system against CRC, due to their different immunoglobulin isotypes. Although anti-EGFR antibodies are efficient, drug resistance occurs with high frequency. Resistant tumor cell populations can either already be present before therapy or develop later by biochemical adaptations or new genomic mutations in the EGFR pathway. Numerous efforts have been made to improve the efficacy of the anti-EGFR mAbs or to find new agents that are able to block downstream EGFR signaling cascade molecules. Indeed, we examined the importance of analyzing the anti-EGFR antibody-drug conjugates (ADC) developed to overcome resistance and/or stimulate the tumor host\'s immunity against CRC growth. Also, patient-derived CRC organoid cultures represent a useful and feasible in vitro model to study tumor behavior and therapy response. Organoids can reflect tumor genetic heterogeneity found in the tissue of origin, representing a unique tool for personalized medicine. Thus, CRC-derived organoid cultures are a smart model for studying the tumor microenvironment and for the preclinical assay of anti-EGFR drugs.
摘要：
结直肠癌（CRC）是全球癌症相关死亡的第二大原因。因此,对新的治疗策略的需求仍然是一个挑战.手术和化疗是一线干预措施；尽管如此，转移性CRC(mCRC)患者的预后仍不可接受.靶向治疗的重要步骤来自表皮生长因子受体（EGFR）途径的抑制，通过抗EGFR抗体，西妥昔单抗,或特异性酪氨酸激酶抑制剂（TKI）。西妥昔单抗,小鼠-人嵌合单克隆抗体（mAb），与EGFR的胞外结构域结合，从而损害EGFR介导的信号传导并减少细胞增殖。TKI可以在信号级联的不同步骤影响EGFR生化途径。除了西妥昔单抗,已经开发了其他抗EGFR单克隆抗体，如帕尼单抗。两种抗体均已被批准用于治疗KRAS-NRAS野生型mCRC，单独或与化疗联合使用。这些抗体在激活宿主免疫系统对抗CRC方面表现出强烈的差异，由于它们不同的免疫球蛋白同种型。尽管抗EGFR抗体是有效的，耐药性发生频率高。抗性肿瘤细胞群体可以在治疗之前已经存在,或者通过EGFR途径中的生化适应或新的基因组突变在以后发展。已经做出了许多努力来改善抗EGFR单克隆抗体的功效或发现能够阻断下游EGFR信号传导级联分子的新试剂。的确,我们研究了分析抗EGFR抗体-药物偶联物(ADC)的重要性,这些偶联物用于克服耐药性和/或刺激肿瘤宿主对CRC生长的免疫力.此外，源自患者的CRC类器官培养物代表了研究肿瘤行为和治疗反应的有用且可行的体外模型.类器官可以反映起源组织中发现的肿瘤遗传异质性，代表个性化医疗的独特工具。因此，CRC衍生的类器官培养是研究肿瘤微环境和抗EGFR药物临床前测定的智能模型。
