Genentech, South San Francisco, California 94080, USA.
Clin Cancer Res. 2011 May 15;17(10):3378-87. doi: 10.1158/1078-0432.CCR-10-3370. Epub 2011 May 10.
Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened.
In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in Ptch1 (+/-) K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days.
In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study.
Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent.
Hedgehog（Hh）信号通路在皮肤中的异常激活对基底细胞癌（BCC）的发展至关重要。我们研究了局部应用 Hh 信号转导分子 Smoothened 抑制剂 CUR61414 对 BCC 的抑制作用。
在临床前研究中，我们使用脱毛模型评估 CUR61414 的局部制剂抑制正常皮肤毛囊底部发现的 Hh 反应性细胞的能力。我们还测试了局部 CUR61414 对 Ptch1（+/-）K14-CreER2 p53 fl/fl 小鼠中形成的鼠 BCC 的体内作用。在 I 期临床试验中，我们评估了 0.09%、0.35%、1.1%和 3.1%的 CUR61414 多剂量方案（局部应用）治疗人类浅表或结节性 BCC 长达 28 天的安全性、耐受性和疗效。
在小鼠中，局部 CUR61414 显著抑制皮肤 Hh 信号，阻止毛囊再生诱导，并缩小现有的 BCC。然而，在 I 期临床试验中，我们未观察到该制剂在人类浅表或结节性 BCC 中的临床活性。
我们的数据突出了将临床前经验转化为局部抗癌药物成功的人类结果所面临的一些挑战。
