The Hedgehog pathway and its inhibitors: Emerging therapeutic approaches for basal cell carcinoma

Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer (NMSC). Although surgery is the first-line treatment, BCC can lead in some cases, to a metastatic or advanced form, requiring targeted combination therapies. The Hedgehog (Hh) signalling pathway is the major pathway associated with the formation of basal carcinoma tumorigenesis, thus, targeting this is a promising therapeutic approach. Some Hh inhibitors have been approved by the US Food and Drug Administration (FDA), such as vismodegib and sonidegib. However, both of these showed limited effectiveness against resistant tumors. Therefore, an essential understanding of the mechanisms involved in the Hh signaling pathway is necessary to improve tumor inhibition.     

浅谈Hedgehog信号通路与肿瘤的相关性

摘 要 Hedgehog信号通路的发现始于对果蝇胚胎发育的研究,其对细胞的生长增殖、分化和组织发育起关键作用。众多研究表明该通路与多种肿瘤有关,包括基底细胞癌,前列腺癌,胰腺癌,胃癌和肺癌等。抑制该通路的异常激活有可能成为肿瘤预防、诊断、治疗及预后的新靶点。     

Recent advances in the design of Hedgehog pathway inhibitors for the treatment of malignancies

Introduction: The Hedgehog (Hh) signaling pathway is known to be dysregulated in several forms of cancer. Hence, specifically targeting this signaling cascade is a valid and promising strategy for successful therapeutic intervention. Several components within the Hh pathway have been proven to be druggable; however, challenges in the discovery and development process for small molecules targeting this pathway have been identified.

Areas covered: This review details both the current state and future potential of Hh pathway inhibitors as anticancer chemotherapeutics that target a variety of human malignancies.

Expert opinion: The initial development of Hh pathway inhibitors focused on small-molecule antagonists of Smoothened, a transmembrane protein that is a key regulator of pathway signaling. More recently, efforts to identify and develop inhibitors of pathway signaling that function through alternate mechanisms have been increasing. However, none of these have advanced into clinical trials. Further, early evidence suggesting the broad application of Hh pathway inhibitors as a monotherapy in a wide range of human cancers has not been validated. The potential for Hh pathway inhibitors as combination therapy has demonstrated promising preclinical results. However, more research to identify rational drug combinations to fully explore the potential of this anticancer drug class is warranted.     

Dynamic thiol/disulphide homeostasis in patients with basal cell carcinoma

Background: The aim of this study is to measure and compare the dynamic thiol/disulphide homeostasis of patients with basal cell carcinoma and healthy subjects with a newly developed and original method.

Objective: Thirty four patients attending our outpatient clinic and clinically and histopathologically diagnosed as nodular basal cell carcinoma, and age and gender matched 30 healthy individuals have been involved in the study. Thiol/disulphide homeostasis tests have been measured with a novel automatic spectrophotometric method developed and the results have been compared statistically.

Results: Serum native thiol and disulphide levels in the patient and control group show a considerable variance statistically (p?=?0.028, 0.039, respectively). Total thiol levels do not reveal a considerable variation (p?=?0.094). Disulphide/native thiol ratios and native thiol/total thiol ratios also show a considerable variance statistically (p?=?0.012, 0.013, 0.010, respectively).

Conclusions: Thiol disulphide homeostasis in patients with basal cell carcinoma alters in the way that disulphide gets lower and thiols get higher. Thiol/disulphide level is likely to have a role in basal cell carcinoma pathogenesis.     

基底细胞癌复发风险水平分析

目的 探讨基底细胞癌(BCC)复发风险的水平和特点.方法 选取67例经组织病理学确诊及临床资料完整的皮肤基底细胞癌患者为研究对象,回顾性分析基底细胞癌部位/大小、病理亚型等资料.结果 67例患者中男女比例为0.76:1;发病平均年龄为(68.6±11.36)岁;入选患者均为原发单发病例.发病部位:头颈部56例,躯干四肢...     

Sonidegib for the treatment of advanced basal cell carcinoma

Introduction: Advanced and metastatic basal cell carcinomas (BCCs) are rare but still present a severe medical problem. These tumors are often disfiguring and impact the quality of life by pain or bleeding. Based on discovery of the hedgehog (Hh) signaling pathway and its role in the pathogenesis of BCCs, smoothened (SMO) inhibitors have been developed with Sonidegib being the 2nd in class. It is the only Hh pathway inhibitor investigated in a randomized trial accompanied by pharmacodynamic investigations. Also, the disease assessment criteria applied were more stringent than those used in trials of 1st developed SMO inhibitor – vismodegib, and required annotated photographs, MRI as well as multiple biopsies in case of regression.

Areas covered: All available papers from Medline and the abstracts of the most important dermato-oncology meetings were included.

Expert opinion: Sonidegib is a promising medication for advanced BCC and other malignancies, driven by Hh signaling. It presents favorable pharmacokinetic properties and causes class specific toxicity with dose dependent adverse events in muscular and taste bud homeostasis, gastrointestinal symptoms and hair growth. Early after treatment initiation, it impacts the immunesusceptibility of the tumor lesions. Sonidegib deserves further development in combination with other drugs or antibodies, or alternative dosing schedules.     

Unusual localization of a common cutaneous neoplasm: basal cell carcinoma

Basal cell carcinoma (BCC) is the most common form of the skin carcinomas and ultraviolet radiation is the major risk factor in the etiopathogenesis. However, reports of unusual sites for BCC are increased in the literature. Authors draw attention to possibility of other etiological agents for BCC like local trauma, ageing, ionizing radiation, arsenic, chronic inflammation, and immune deficiency. Here, we reported a 74-year-old male patient with nodular BCC on groin. We thought that ageing or local trauma may have a role in its formation.     

5-氨基酮戊酸光动力疗法联合咪喹莫特治疗基底细胞癌疗效观察

目的 评价5-氨基酮戊酸光动力疗法（ALA-PDT）与咪喹莫特联合治疗基底细胞癌的疗效.方法 将38例基底细胞癌患者随机分为两组,各19例.治疗组采用ALA-PDT与咪喹莫特联合治疗,对照组单用ALA-PDT.所有患者随访一年,观察两组疗效和复发率.结果 治疗组患者痊愈率为94.74%（18/19）,复发率为5.26%（1/19） 对照组痊愈率为68.42%（13/19）,复发率为31.58%（6/19）.两组痊愈率及复发率差异有统计学意义（x2=4.37,P〈0.05）.结论 ALA-PDT联合咪喹莫特治疗基底细胞癌在疗效及复发率方面均明显优于单用ALA-PDT.     

51例基底细胞癌初诊误诊分析

目的 分析51例基底细胞癌初诊误诊情况,提高诊断水平,避免误诊、漏诊。 方法 回顾性分析51例基底细胞癌初步诊断误诊病人临床及组织病理资料。 结果 51例病人诊断为基底细胞癌待查3例,包块性质待查29例,皮肤溃疡5例,误诊色素痣4例,鳞状细胞癌3例,脂溢性角化症2例,血管瘤2例,恶性黑色素瘤2例,皮脂腺囊肿1例。临床分型:结节溃疡型37例,色素型11例,纤维上皮瘤型2例,浅表型1例。病理分型:实体型31例,色素型14例,浅表型1例,硬化型2例,囊样型2例,腺样型1例。 结论 基底细胞癌皮损多样,易误诊。积累临床经验,仔细查体,结合皮肤镜检查可减少误诊的发生,确诊需要行组织病理检查。     

ALA-PDT联合高频电灼治疗基底细胞癌的疗效观察及护理

目的 探讨5-氨基酮戊酸光动力疗法（ALA-PDT）结合高频电灼治疗基底细胞癌的疗效及护理体会.方法 对40例基底细胞癌患者,根据个体的皮损状况给予ALA-PDT联合高频电灼治疗,同时给予良好的护理及指导,对完全缓解的病例进行为期6个月的随访.结果 经过5～15次的治疗和良好的护理后,完全缓解31例（77.5％）,部分缓解4例（10.0％）,无效5例（12.5％）,总有效率为87.5％;美容效果满意度评价中,满意29例（72.5％）、一般满意4例（10.0％）、不满意7例（17.5％）;31例完全缓解的患者随访6个月,有4例（12.9％）复发;所有病例均未出现感染、创口愈合不良.结论 ALA-PDT结合高频电灼治疗对基底细胞癌疗效优越,结合良好的护理措施,可以提高治疗效果,增加患者对治疗的满意度.     

COX-2、PTEN在皮肤基底细胞癌中的表达与临床意义

目的探讨皮肤基底细胞癌（basal cell carcinoma,BCC）组织中COX-2和PTEN的表达情况及临床意义。方法采用免疫组SP法检测58例基底细胞癌组织和20例正常对照组织中COX-2和PTEN的表达情况。结果 C0X-2蛋白在正常皮肤中阳性表达率为15%,在BCC中呈高表达,阳性表达率为60.3%,其差异有统计学意义（P〈0.01）;PTEN蛋白在正常皮肤组织中阳性表达率为90.0%,而在BCC中表达明显减弱,阳性表达率仅为17.2%,其差异也具有统计学意义（P〈0.01）;且COX-2的表达与PTEN的表达呈显著负相关（r=-0.376）。结论 PTEN蛋白在BCC中的低表达,COX-2蛋白在BCC中的高表达,且两者的表达呈负相关,提示二者可能共同参与细胞基底细胞癌的发病过程。     

Novel molecular targets for the therapy of urothelial carcinoma

Introduction: First-line platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma; however, long-term outcomes including disease-specific and overall survival remain suboptimal. In addition, approximately 40 – 50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy. Improvements in our understanding of the molecular mechanisms of urothelial tumorigenesis have led to first-generation clinical trials evaluating novel agents targeting molecular pathways. These are particularly relevant in regard to subpopulations. Novel trial designs warrant consideration to accelerate accrual.

Areas covered: In this review, novel molecular targets for the therapy of urothelial carcinoma, as well as recently completed and ongoing clinical trials utilizing novel targeted agents, are discussed. A Medline search with key words, abstracts reported at national conferences on urothelial carcinoma and NCI clinical trial identifiers was used for this review.

Expert opinion: Improved understanding of molecular biology has identified a number of new molecular targets, but there is a seeming absence of one dominant molecular driver for urothelial cancer. An adaptive and biomarker-derived strategy may be warranted. Clinical trials utilizing targeted agents are ongoing and results are awaited.     

Nonsyndromic multiple basal cell carcinomas successfully treated with imiquimod 5% cream

This report describes the case of a 60-year-old man with nonsyndromic multiple basal cell carcinomas that responded to imiquimod 5% cream. The patient had no additional anomalies suggesting any syndromes associated with multiple basal cell carcinomas. By applying the agent 5 times a week for 20 weeks, we obtained good clinical results, and we confirmed the improvement with histopathologic examination. We suggest that patients with multiple basal cell carcinomas should be interviewed about and tested for the associated syndromes, and topical imiquimod should be kept in mind as an alternative therapy choice in these patients.     

纳米二氧化钛对人皮肤基底细胞癌和胚胎皮肤成纤维细胞的生物学效应

目的探讨纳米粒子二氧化钛(TiO2)对体外培养的人皮肤基底细胞癌A431和人胚胎皮肤成纤维细胞的生物学效应。方法TiO2处理体外培养的人皮肤基底细胞癌A431(human skin Basal cell carcinoma,A431)和人胚胎皮肤成纤维细胞(human embryo skin Fibroblast,ESF),MTT法测定细胞生长活性,计数集落形成和荧光染色检测细胞凋亡情况。结果纳米TiO2显著抑制体外培养的人皮肤基底细胞癌A431的集落形成,对其生长活性具有显著负相关性(P<0.05);能够抑制人胚胎皮肤成纤维细胞(ESF)的集落形成,但对其生长活性的抑制无相关性(P>0.05)。结论纳米TiO2可影响体外培养的人皮肤基底细胞癌A431的生长、集落形成,并可导致细胞凋亡。     

Fangchinoline as a kinase inhibitor targets FAK and suppresses FAK-mediated signaling pathway in A549

Background: Fangchinoline as a novel anti-tumor agent has been paid attention in several types of cancers cells except lung cancer. Here we have investigated the effect of fangchinoline on A549 cells and its underlying mechanism.

Purpose: The purpose of this work was to study the effect of fangchinoline on A549 cells.

Methods: Four lung cancer cell lines (A549, NCI-H292, NCI-H446, and NCI-H460) were exposed to varying concentrations (10–40?μmol/l) of fangchinoline to observe the effect of fangchinoline on the four lung cancer cell lines and to observe the changes of the lung cancer cell on proliferation, apoptosis, and invasion.

Results: Fangchinoline effectively suppressed proliferation and invasion of A549 cell line but not NCI-H292, NCI-H446, and NCI-H460 cell lines by inhibiting the phosphorylation of FAK (Tyr397) and its downstream pathways, due to the significant differences of Fak expression between A549 and the other three cell lines. And all FAK-paxillin/MMP2/MMP9 pathway, FAK-Akt pathway, and FAK-MEK-ERK1/2 pathway could be inhibited by fangchinoline.

Discussion: Fangchinoline effectively suppressed proliferation and invasion of A549 cell line by inhibiting the phosphorylation of FAK (Tyr397) and its downstream pathways.

Conclusion: Fangchinoline could inhibit the phosphorylation of FAK^p-Tyr397, at least partially. Fangchinoline as a kinase inhibitor targets FAK and suppresses FAK-mediated signaling pathway and inhibits the growth and the invasion in tumor cells which highly expressed FAK such as A549 cell line.     

Identification of Vitamin D3-Based Hedgehog Pathway Inhibitors That Incorporate an Aromatic A-Ring Isostere

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氨基酮戊酸光动力疗法治疗基底细胞癌1例

基底细胞癌（BCC）是一种较常见的皮肤恶性肿瘤,主要发生在老年人群,好发于头皮和面部等暴露部位。该病多见于户外工作和浅色皮肤者,可能与长期日光照射有关,损害多表现为浅表型皮疹[1]。目前临床上首选手术切除治疗,但是由于某些病变部位的特殊性,或因手术难度高、涉及美容难以获得令人满意效果、可能对器官功能等产生不同程度的损伤等原因手术常不易被患者接受。     

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