Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma.
Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma.
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DOI：
10.2147/jep.s28553
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发表时间：
2012
影响因子：
--
通讯作者：
De Smaele E
中科院分区：
文献类型：
--
作者：
Cucchi D;Occhione MA;Gulino A;De Smaele E
皮肤基底细胞癌（BCC）是最常见的癌症类型，占美国所有癌症的40%，近几十年来，所有发达国家的发病率都在不断上升。手术可以治愈大多数患者，尽管它会留下不美观的疤痕，但那些发展为局部晚期或转移性BCC的患者需要不同的治疗方法。此外，BCC患者发展为其他肿瘤的风险很高。日益增加的经济负担和BCC的发病率使人们对这种疾病的靶向治疗的发展产生了主要的兴趣。在参与BCC发展的分子信号中，形态发生Hedgehog （Hh）通路的关键作用已经变得明显。该通路在几乎所有散发性和遗传性bcc中都被改变和激活。鉴于Hh通路在BCC病理生理中的中心地位，确定局部或全身治疗这种癌症的分子靶点的主要努力集中在Hh组分上。到目前为止，已经发现了几种Hh抑制剂——从第一个发现的天然环巴胺到最近获得美国食品和药物管理局批准的合成vismodegib——其中大多数靶向Hh受体平滑（其功能或其向初级纤毛的易位）。其他分子有待进一步鉴定（双酰胺化合物），而目前批准用于其他疾病的药物，如伊曲康唑（一种抗菌剂）和维生素D3，已在BCC上进行了测试，结果令人鼓舞。众多正在进行的临床试验的结果有望在不久的将来扩大这一领域。为了克服潜在的耐药性，需要进一步的研究来获得针对Hh通路下游组分（如Gli）的药物或开发联合治疗（如与磷脂酰肌醇3-激酶抑制剂或类维生素a）。
Basal cell carcinoma (BCC) of the skin is the most common type of cancer and accounts for up to 40% of all cancers in the US, with a growing incidence rate over recent decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutic approaches. Furthermore, patients with BCC present a high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render primary interest in the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, the critical role of the morphogenetic Hedgehog (Hh) pathway has become evident. This pathway is found altered and activated in almost all BCCs, both sporadic and inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hh components. Several Hh inhibitors have been so far identified – from the first identified natural cyclopamine to the recently Food and Drug Administration-approved synthetic vismodegib – most of which target the Hh receptor Smoothened (either its function or its translocation to the primary cilium). Other molecules await further characterization (bisamide compounds), while drugs currently approved for other diseases such as itraconazole (an antimicotic agent) and vitamin D3 have been tested on BCC with encouraging results. The outcomes of the numerous ongoing clinical trials are expected to expand the field in the very near future. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg, Gli) or to exploit combinatorial therapies (eg, with phosphatidylinositol 3-kinase inhibitors or retinoids) in order to overcome potential drug resistance.