Pilié Patrick, Hasanov Elshad, Matin Surena F, Woodson Ashley H Henriksen, Marcott Valerie D, Bird Shelly, Slack Rebecca S, Fuller Gregory N, McCutcheon Ian E, Jonasch Eric
Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Oncotarget. 2018 May 4;9(34):23390-23395. doi: 10.18632/oncotarget.25171.
Von Hippel-Lindau (VHL) disease is an autosomal dominant disease occurring in 1 in 35,000 births and leads to an increased risk of a phenotypically diverse array of tumor types including, but not limited to, clear cell renal cell carcinoma (ccRCC) and hemangioblastomas (HBs). Previous studies of patients with VHL disease treated with the tyrosine kinase inhibitor (TKI) sunitinib did not show clinical response in HBs. Interestingly, VHL-related HBs displayed increased fibroblast growth factor receptor 3 (FGFR3) protein expression when compared to VHL-related ccRCCs. Therefore, in this pilot study, we assessed the safety and efficacy profile of TKI 258 (dovitinib), a multi-tyrosine kinase inhibitor of VEGF receptor and fibroblast growth factor (FGF), in patients with VHL disease who had measureable HBs. The trial was stopped after six patients enrolled after the toxicity stopping rule was triggered. With regards to safety, 6/6 subjects had at least one adverse event (AE). Best response in 6/6 subjects was stable disease (SD) in HBs. While the negative safety and efficacy results of this pilot study do not favor the use of dovitinib for the treatment of asymptomatic HBs in VHL disease patients, further investigation into alternative scheduling and other FGFR inhibitors for the treatment of HBs in VHL disease patients is warranted given the promising pre-clinical and molecular data.
冯·希佩尔-林道（VHL）病是一种常染色体显性疾病，发病率为1/35000，会增加患多种不同表型肿瘤的风险，包括但不限于透明细胞肾细胞癌（ccRCC）和血管母细胞瘤（HB）。此前对接受酪氨酸激酶抑制剂（TKI）舒尼替尼治疗的VHL病患者的研究未显示其对HB有临床反应。有趣的是，与VHL相关的ccRCC相比，VHL相关的HB显示成纤维细胞生长因子受体3（FGFR3）蛋白表达增加。因此，在这项初步研究中，我们评估了TKI 258（多韦替尼）——一种VEGF受体和成纤维细胞生长因子（FGF）的多酪氨酸激酶抑制剂——对患有可测量HB的VHL病患者的安全性和疗效。在6名患者入组后触发毒性停止规则，试验停止。关于安全性，6/6的受试者至少有1次不良事件（AE）。6/6受试者的最佳反应是HB病情稳定（SD）。虽然这项初步研究的安全性和疗效阴性结果不支持使用多韦替尼治疗VHL病患者的无症状HB，但鉴于有前景的临床前和分子数据，有必要进一步研究替代给药方案和其他FGFR抑制剂用于治疗VHL病患者的HB。
