Targeting BRAFV600E in an Inducible Murine Model of Melanoma
Targeting BRAFV600E in an Inducible Murine Model of Melanoma
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DOI：
10.1016/j.ajpath.2012.06.002
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发表时间：
2012-09-01
影响因子：
6
通讯作者：
Blank, Christian U.
中科院分区：
文献类型：
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作者：
Hooijkaas, Anna I.;Gadiot, Jules;Blank, Christian U.
MAP激酶和PI 3激酶途径已被鉴定为介导黑素瘤中致癌转化的最常见途径，并且开发用于黑素瘤治疗的大多数化合物靶向这些途径中的一种或另一种。除了此类靶向疗法外，免疫治疗方法也显示出了有希望的结果。两种治疗方式的结合可能会进一步改善治疗结果。为了在临床前确定有效的治疗组合并在顺序和时间方面优化治疗方案，将需要小鼠模型。我们已经穿越并描述了提尔河：CreER（T2）;PTENF-/-;BRAF（F-V600 E/+）可诱导的黑素瘤模型在C57 BL/6 J背景上。该模型中的肿瘤含有BRAF（V600 E）突变并且是PTEN缺陷的，使其非常适合用于靶向疗法的测试。此外，我们将该模型交叉到该特定背景中用于免疫治疗研究，因为该领域的大多数实验都是在C57 BL/6 J小鼠中进行的。PLX 4720治疗荷黑色素瘤小鼠选择性抑制BRAF（V600 E）导致肿瘤生长强烈减少。此外，诱导型黑色素瘤具有与人黑色素瘤中发现的免疫细胞浸润相似的免疫细胞浸润，并且可以从这些肿瘤中培养肿瘤浸润淋巴细胞。我们的数据表明，C57 BL/6 J Tyr.：creER（T2）; PTENF-/-; BRAF（F-V600 E/+）黑色素瘤模型可以用作标准模型，其中可以以高通量方式测试靶向和免疫治疗组合。(Am J Pathol 2012，181：785-794; http：//dx·doi·org/10·1016/j·ajpath·2012·06·002）
The MAP kinase and PI3 kinase pathways have been identified as the most common pathways that mediate oncogenic transformation in melanoma, and the majority of compounds developed for melanoma treatment target one or the other of these pathways. In addition to such targeted therapies, immunotherapeutic approaches have shown promising results. A combination of the two treatment modalities could potentially result in further improvement of treatment outcome. To preclinically identify efficient treatment combinations and to optimize therapy protocols in terms of sequence and timing, mouse models will be required. We have crossed and characterized the Tyr.:CreER(T2);PTENF-/-;BRAF(F-V600E/+) inducible melanoma model on a C57BL/6J background. Tumors from this model harbor the BRAF(V600E) mutation and are PTEN-deficient, making them highly suitable for the testing of targeted therapies. Furthermore, we crossed the model onto this specific background for use in immunotherapy studies, because most experiments in this field have been performed in C57BL/6J mice. Selective inhibition of BRAF(V600E) by PLX4720 treatment of melanoma-bearing mice resulted in a strong decrease of tumor outgrowth. Furthermore, the inducible melanomas had immune cell infiltrates similar to those found in human melanoma, and tumor-infiltrating lymphocytes could be cultured from these tumors. Our data indicate that the C57BL/6J Tyr.:CreER(T2);PTENF-/-;BRAF(F-V600E/+) melanoma model could be used as a standard model in which targeted and immunotherapy combinations can be tested in a high-throughput manner. (Am J Pathol 2012, 181:785-794; http://dx.doi.org/10.1016/j.ajpath.2012.06.002)