晚期基底细胞癌中hedgehog途径的抑制。
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Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, yuch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC JR, de Sauvage FJ, Low JA
晚期基底细胞癌中hedgehog途径的抑制。
中华外科杂志2009 9月17日;361(12):1164-72。doi: 10.1056 / NEJMoa0905360。Epub 2009 9月2日。
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19726763 (PubMed视图］
- 摘要
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背景:hedgehog途径基因突变，主要是编码补丁同源体1 (PTCH1)和平滑同源体(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对该药物的反应。方法:我们选择了33例转移性或局部晚期基底细胞癌患者接受口服GDC-0449，剂量为三种之一;17例患者每天接受150毫克，15例患者每天接受270毫克，1例患者每天接受540毫克。我们使用实体瘤反应评价标准(RECIST)、体检或两者结合来评估肿瘤反应。对肿瘤的分子方面进行了检查。结果:研究治疗的中位持续时间为9.8个月。在33例患者中，根据影像学评估(7例)、体检评估(10例)或两者评估(1例)，18例患者对GDC-0449有客观反应。在有反应的患者中，2例有完全反应，16例有部分反应。其余15例患者病情稳定(11例)或进展(4例)。 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.)
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