Wang Yannick, Wozniak Agnieszka, Wellens Jasmien, Gebreyohannes Yemarshet K, Guillén Maria Jose, Avilés Pablo M, Debiec-Rychter Maria, Sciot Raf, Schöffski Patrick
Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
Transl Oncol. 2020 Nov;13(11):100832. doi: 10.1016/j.tranon.2020.100832. Epub 2020 Jul 22.
The majority of patients with gastrointestinal stromal tumors (GIST) eventually become resistant with time due to secondary mutations in the driver receptor tyrosine kinase. Novel treatments that do not target these receptors may therefore be preferable. For the first time, we evaluated a tubulin inhibitor, plocabulin, in patient-derived xenograft (PDX) models of GIST, a disease generally considered to be resistant to cytotoxic agents. Three PDX models of GIST with different KIT genotype were generated by implanting tumor fragments from patients directly into nude mice. We then used these well characterized models with distinct sensitivity to imatinib to evaluate the efficacy of the novel tubulin inhibitor. The efficacy of the drug was assessed by volumetric analysis of the tumors, histopathology, immunohistochemistry and Western blotting. Plocabulin treatment led to extensive necrosis in all three models and significant tumor shrinkage in two models. This histological response can be explained by the drug's vascular-disruptive properties, which resulted in a shutdown of tumor vasculature, reflected by a decreased total vascular area in the tumor tissue. Our results demonstrated the in vivo efficacy of the novel tubulin inhibitor plocabulin in PDX models of GIST and challenge the established view that GIST are resistant to cytotoxic agents in general and to tubulin inhibitors in particular. Our findings provide a convincing rationale for early clinical exploration of plocabulin in GIST and warrant further exploration of this class of drugs in the management of this common sarcoma subtype.
大多数胃肠道间质瘤（GIST）患者最终会随着时间的推移因驱动受体酪氨酸激酶的二次突变而产生耐药性。因此，不靶向这些受体的新型治疗方法可能更可取。我们首次在GIST的患者来源异种移植（PDX）模型中评估了一种微管蛋白抑制剂——普罗卡布林，GIST通常被认为对细胞毒性药物耐药。通过将患者的肿瘤碎片直接植入裸鼠体内，建立了三种具有不同KIT基因型的GIST PDX模型。然后，我们使用这些对伊马替尼具有不同敏感性的特征明确的模型来评估新型微管蛋白抑制剂的疗效。通过肿瘤体积分析、组织病理学、免疫组织化学和蛋白质印迹法评估药物疗效。普罗卡布林治疗在所有三种模型中均导致广泛坏死，在两种模型中肿瘤显著缩小。这种组织学反应可以用该药物的血管破坏特性来解释，这导致肿瘤血管关闭，表现为肿瘤组织中总血管面积减少。我们的结果证明了新型微管蛋白抑制剂普罗卡布林在GIST的PDX模型中的体内疗效，并挑战了GIST总体上对细胞毒性药物耐药，尤其是对微管蛋白抑制剂耐药的既定观点。我们的研究结果为普罗卡布林在GIST中的早期临床探索提供了令人信服的理论依据，并值得在这种常见肉瘤亚型的治疗中进一步探索这类药物。
