Genetically Engineered Cancer Models, But Not Xenografts, Faithfully Predict Anticancer Drug Exposure in Melanoma Tumors

Background. Rodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed. Methods. In this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs). Results. Using microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors. Conclusions. The tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors. 摘要 背景. 啮齿类动物研究作为抗癌新型疗法发展里程中的关键步骤，用于药物代谢动力学（ PK）、毒理学以及疗效研究。传统抗癌药物研发依赖于在免疫缺陷小鼠中移植人类癌细胞系的异种移植物，进而对候选化合物进行疗效筛查。然而，异种移植物模型在疗效检测方面的有效性已受到质疑，而基因工程小鼠模型（ GEMM）和原位同基因移植（ OST ）可能在疗效评估方面具有一定优势。影响啮齿类动物肿瘤模型预测能力的关键因素是药物 PK，但还未在异种移植物模型、 OST 、 GEMM 以及人类患者之间对血浆与肿瘤PK参数进行综合比较。 方法. 本研究评估了治疗黑色素瘤制剂卡铂在血浆与肿瘤的分布，在皮肤黑色素瘤患者与4种不同的小鼠黑色素瘤模型之间进行了比较（1种为 GEMM ，1种为人类细胞系异种移植物，2种为OST）。 结果. 利用微透析技术对卡铂肿瘤分布进行抽样检测，我们发现OST和异种移植物在预测人类肿瘤中的药物暴露方面效果很差，而通过 GEMM 模型检测出的PK参数与在人类肿瘤中观察到的结果相似。 结论. 与移植肿瘤模型相比，卡铂在黑色素瘤 GEMM 中的肿瘤PK能够更好地模拟黑色素瘤患者中的肿瘤分布。 GEMM 有望成为一种改进的预测模型，用于预测瘤内PK以及实体瘤患者的治疗反应。 The plasma and tumor dispositions of a commonly used antimelanoma agent, carboplatin, were evaluated in patients with cutaneous melanoma and compared with four different murine melanoma models (one genetically engineered mouse model, one human cell line xenograft, and two orthotopic syngeneic transplant models). The tumor pharmacokinetics of carboplatin