Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma.
Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma.
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DOI：
10.1056/nejmoa0905360
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发表时间：
2009-09-17
影响因子：
158.5
通讯作者：
Low, Jennifer A.
中科院分区：
文献类型：
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作者：
Von Hoff, Daniel D.;LoRusso, Patricia M.;Low, Jennifer A.
背景：Hedgehog通路基因的突变，主要是编码补丁同源1(Ptch1)和平滑同源基因(SMO)的基因，发生在基底细胞癌中。在一期临床试验中，我们评估了SMO的小分子抑制剂GDC-0449的安全性和药代动力学，以及转移性或局部晚期基底细胞癌患者对该药物的反应。方法：我们选择33例转移性或局部晚期基底细胞癌患者给予三种剂量之一的GDC-0449，17例患者每天服用150 mg，15例患者每天服用270 mg，1例患者每天服用540 mg。我们使用实体肿瘤反应评估标准(RECIST)、体格检查或两者兼而有之来评估肿瘤反应。结果：研究治疗的中位持续时间为9.8个月。在33名患者中，根据影像(7名患者)、体检(10名患者)或两者兼有(1名患者)的评估，18名患者对GDC-0449有客观反应。在有反应的患者中，2例完全缓解，16例部分缓解。其余15例均为稳定期(11例)或进展期(4例)。在6名患者中报告了8起被认为可能与研究药物有关的3级不良事件，包括4名疲劳、2名低钠血症、1名肌肉痉挛和1名房颤。1个4级事件，无症状低钠血症，被判断与GDC-0449无关。一名患者因不良事件而退出研究。我们在对治疗有反应的肿瘤中发现了Hedgehog信号的证据。结论：针对Hedgehog途径的口服活性小分子GDC-0449在局部晚期或转移性基底细胞癌中似乎具有抗肿瘤活性。(ClinicalTrials.gov编号，NCT00607724)N Engl J Med 2009；361：1164-72。
Background: Mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety and pharmacokinetics of GDC-0449, a small-molecule inhibitor of SMO, and responses of metastatic or locally advanced basal-cell carcinoma to the drug.Methods: We selected 33 patients with metastatic or locally advanced basal-cell carcinoma to receive oral GDC-0449 at one of three doses; 17 patients received 150 mg per day, 15 patients received 270 mg per day, and 1 patient received 540 mg per day. We assessed tumor responses with the use of Response Evaluation Criteria in Solid Tumors (RECIST), physical examination, or both. Molecular aspects of the tumors were examined.Results: The median duration of the study treatment was 9.8 months. Of the 33 patients, 18 had an objective response to GDC-0449, according to assessment on imaging (7 patients), physical examination (10 patients), or both (1 patient). Of the patients who had a response, 2 had a complete response and 16 had a partial response. The other 15 patients had either stable disease (11 patients) or progressive disease (4 patients). Eight grade 3 adverse events that were deemed to be possibly related to the study drug were reported in six patients, including four with fatigue, two with hyponatremia, one with muscle spasm, and one with atrial fibrillation. One grade 4 event, asymptomatic hyponatremia, was judged to be unrelated to GDC-0449. One patient withdrew from the study because of adverse events. We found evidence of hedgehog signaling in tumors that responded to the treatment.Conclusions: GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma. (ClinicalTrials.gov number, NCT00607724.)N Engl J Med 2009;361:1164-72.