ImClone Systems, Eli Lilly and Company, Department of Preclinical Pharmacology, Alexandria Center for Science and Technology, 450 First Avenue, New York, NY 10016, USA.
Anticancer Res. 2011 Jun;31(6):2149-60.
Clinically relevant targets for developmental drug efficacy in animal models of cancer are critical yet understudied parameters.
Cetuximab, a chimeric antibody to epidermal growth factor receptor (EGFR), was administered to athymic mice bearing subcutaneous tumors established with 13 human colorectal cancer cell lines of varying biomarker status, defined by DNA sequencing and RT-PCR.
If tumor growth inhibition is taken as a target, as is commonly done, then in contrast to the clinical situation where KRAS mutation strongly predicts for a lack of clinically meaningful benefit in colorectal cancer patients, cetuximab alone and in combination with irinotecan-based chemotherapy were efficacious in a similar proportion of KRAS wild-type and mutant models. It was only when tumor regression was utilized to define relevant efficacy that cetuximab monotherapy was efficacious in KRAS wild-type, but not mutant models. Adding cytotoxic therapy to cetuximab treatment increased tumor regression frequency in both genotypes to the point that once again the response was similar for KRAS wild-type and mutant models.
Our data support shifting the threshold for claiming clinically relevant targeted therapy efficacy in subcutaneous xenograft models towards tumor regression, rather than tumor growth inhibition, focusing on the evaluation of tumor cells that are addicted to the pathways being targeted.
在癌症动物模型中，具有临床意义的药物疗效的目标是关键但研究不足的参数。
西妥昔单抗是一种针对表皮生长因子受体（EGFR）的嵌合抗体，用于携带皮下肿瘤的无胸腺小鼠，这些肿瘤是用 13 种具有不同生物标志物状态的人结直肠癌细胞系建立的，通过 DNA 测序和 RT-PCR 定义。
如果将肿瘤生长抑制作为目标，就像通常所做的那样，那么与 KRAS 突变强烈预测结直肠癌患者缺乏临床意义的获益的临床情况相反，西妥昔单抗单药治疗和联合伊立替康化疗在 KRAS 野生型和突变型模型中的疗效相似。只有当利用肿瘤消退来定义相关疗效时，西妥昔单抗单药治疗在 KRAS 野生型模型中才有效，但在突变模型中无效。将细胞毒性疗法添加到西妥昔单抗治疗中，增加了两种基因型的肿瘤消退频率，以至于再次对 KRAS 野生型和突变型模型的反应相似。
我们的数据支持将声称具有临床意义的靶向治疗疗效的阈值从肿瘤生长抑制转移到肿瘤消退，而不是肿瘤生长抑制，重点是评估对被靶向途径成瘾的肿瘤细胞。
