Pathogenesis Of Basal Cell Carcinoma Research Articles

Efficacy and safety of vismodegib: a new therapeutic agent in the treatment of basal cell carcinoma

Introduction: Basal cell carcinoma (BCC) is the most common human malignancy. Treatment options for the minority of patients presenting with locally advanced inoperable or metastatic BCC are very limited. The hedgehog (Hh) pathway plays a crucial role in the pathogenesis of BCC. Recent advances in targeting this pathway have led to the development of a first-in-class, small-molecule oral Hh inhibitor, vismodegib (Erivedge®, Genentech).Areas covered: In this article, we review vismodegib with regard to its mechanism of action, clinical efficacy, safety and tolerability, and we consider the causes of emerging resistance to the drug.Expert opinion: Vismodegib is a welcome addition to the treatment paradigm for BCC. Approval was based on Phase II evidence, the patient number was relatively small, there was no control group or a comparator group and survival data have not been presented so longer term follow-up and larger exposure to the drug is required to fully appreciate its clinical utility into the future. With ongoing use of the drug in the nontrial population and further studies investigating its use in both early- and later-stage disease, we will get a better understanding of the drug and determine its place in the armamentarium against BCC.

The -1154 G/A VEGF gene polymorphism is associated with the incidence of basal cell carcinoma in patients from northern Poland.

Vascular endothelial growth factor (VEGF) is believed to play a crucial role in neoplastic angiogenesis. Although the genetic background of basal cell carcinoma (BCC) has been analyzed in some papers, the mechanism of BCC pathogenesis is not fully understood. To the best of our knowledge, VEGF gene polymorphisms have not yet been explored. The aim of the study was to asses the frequency of three polymorphisms in the VEGF gene (−1154 G/A, −460 T/C and +405 G/C) in patients of Polish origin with BCC and control group. In addition, VEGF serum levels of patients with BCC and controls were measured. The study involved 180 patients (96 women, 84 men) with BCC and a mean age of 68.9 ± 11.8, and 215 healthy age- and sex-matched volunteers. The VEGF polymorphisms at positions −1154 and +405 were analyzed using the amplification refractory mutation system polymerase chain reaction method. To assess the VEGF gene polymorphism at position −460, we used the polymerase chain reaction restriction fragment length polymorphism method. Serum levels of VEGF protein were measured using the ELISA test. The presence of the G allele (GA or GG) in the −1154 VEGF polymorphism was associated with an increased risk of BCC development (OR = 7.28, p < 0.0001). Furthermore, the carriers of the AA genotype in −1154 VEGF polymorphism showed significantly reduced risks of BCC (OR = 0.14, p < 0.0001). It was also shown that the GTC haplotype of VEGF predisposes to BCC development (OR = 1.69, p = 0.013), while the presence of the ATG haplotype significantly reduces this risk (OR = 0.17, p = 0.00001). We have found significantly increased VEGF serum levels among BCC patients, in comparison with the healthy controls (mean 596.7 ± 393.5 pg/ml; range 60.1–931.4 vs. 255.9 ± 174.6 pg/ml; range 42.2–553.0 pg/ml; p < 0.0004). The serum levels of VEGF significantly correlated with tumor size: r = 0.41, p < 0.0001. Our results testify to the importance of −1154 G/A VEGF gene polymorphisms in altering the risk of BCC among the population from northern Poland.

Pigmented Basal Cell Carcinoma: An Unusual Case Report

Basal cell carcinoma (BCC) is the most common type of skin cancer. The primary established risk factor for BCC is ultraviolet sunlight exposure. Ultraviolet radiation-induced cell damage includes single-stranded breaks and point mutations in DNA. There is increasing evidence that the tumor suppressor gene, patch and other members of the sonic hedgehog signal transduction pathway have an important role in the pathogenesis of BCC. Pigmented BCC is a rare variant with few cases described in English literature in which melanin is produced by melanocytes that colonize the tumor and is present in melanophages located in the surrounding stroma. This paper presents an unusual case of pigmented basal cell carcinoma clinically resembling melanoma.

Precision medicine and precision therapeutics: hedgehog signaling pathway, basal cell carcinoma and beyond.

Precision medicine and precision therapeutics is currently in its infancy with tremendous potential to improve patient care by better identifying individuals at risk for skin cancer and predict tumor responses to treatment. This review focuses on the Hedgehog signaling pathway, its critical role in the pathogenesis of basal cell carcinoma, and the emergence of targeted treatments for advanced basal cell carcinoma. Opportunities to utilize precision medicine are outlined, such as molecular profiling to predict basal cell carcinoma response to targeted therapy and to inform therapeutic decisions.

Sites of Basal cell carcinomas and head and neck congenital clefts: topographic correlation.

Background:The embryologic fusion planes might be related with the sites of onset of basal cell carcinoma (BCC), thus supporting an embryologic role for its pathogenesis.Methods:A study involving 495 patients with 627 BCCs of the head and neck was carried out over a period of 5 years by correlating the distribution of all BCCs with the sites of congenital clefts of the head and neck using (1) the original anatomic diagram of the Tessier classification of craniofacial clefts, (2) the anatomic diagram by Moore et al featuring the paths of the “hairline indicators” of craniofacial clefts that represent the cranial extensions of the Tessier classification, and (3) an anatomical diagram featuring the sites of congenital clefts of the neck.Results:The proportion of BCCs localized within a cleft site was significantly higher than those in the noncleft sites. The age of patients with BCCs localized within the Tessier cleft number 3 was the lowest among all cleft regions.Conclusions:A topographic correspondence between the sites of BCCs and the sites of congenital clefts was demonstrated in the head and neck. This evidence would support the hypothesis of an embryologic role for the pathogenesis of BCC. The existence of clusters of embryological stem cells in the sites of fusion and/or merging of embryonic processes might therefore be proposed. There may be special biology/physiology along these cleft lines that predispose BCC formation.

NL-103, a novel dual-targeted inhibitor of histone deacetylases and hedgehog pathway, effectively overcomes vismodegib resistance conferred by Smo mutations.

Misregulation of hedgehog (Hh) signaling has been implicated in the pathogenesis of basal cell carcinoma (BCC) and medulloblastoma. Vismodegib, an orally bioavailable Hh signal pathway inhibitor targeting Smo, has been approved for the treatment of advanced BCC. However, acquired drug resistance to vismodegib induced by point mutation in Smo is emerging as a major problem to vismodegib treatment. In this study, we designed and synthesized a novel chimeric compound NL-103, which comprises structural elements of Hh pathway inhibitor vismodegib, and histone deacetylase (HDAC) inhibitor vorinostat. NL-103 simultaneously and significantly inhibited both HDACs and Hh pathway. Importantly, NL-103, as well as vorinostat, effectively overcame vismodegib resistance induced by Smoothened point mutations. Moreover, NL-103 and vorinostat, but not vismodegib, significantly downregulated the expression of Gli2 which plays an important role in Hh pathway. These results indicate that HDAC inhibitory activity is essential for NL-103 to overcome vismodegib resistance and that dual inhibition of HDAC and Hh signaling pathway may be a rational strategy for overcoming vismodegib resistance. Our findings suggest that NL-103 may be a promising compound for clinical development as a more effective Hh pathway inhibitor.

Silencing of the cell cycle checkpoint gene 14‐3‐3σ in basal cell carcinomas correlates with reduced expression of IKK‐α

14-3-3σ is down-regulated in a large proportion of basal cell carcinomas (BCC). IkappaB kinase α (IKK-α), one of the two catalytic subunits of the IKK complex involved in NF-kappaB-activation, also functions as a modulator of epidermal development and differentiation. Down-regulation of IKK-α causes hyperplasia and promotes skin cancer. IKK-α has been found to regulate the expression of 14-3-3σ by shielding its promoter from hypermethylation and thereby preventing its silencing in mouse keratinocytes. To evaluate the potential role of IKK-α in the silencing of 14-3-3σ in basal cell carcinoma. Expression of 14-3-3σ and IKK-α was studied by immunohistochemistry in 33 sporadic BCCs and 26 BCCs from patients with basal cell nevus syndrome (BCNS). Marked reduction or absence of 14-3-3σ was found in 24 (92%) BCCs from BCNS patients, and in 29 (88%) sporadic BCCs. Marked reduction or absence of IKK-α was found in 22 (85%) BCCs from patients with BCNS, and in 27 (82%) sporadic BCCs. Expression levels for 14-3-3σ and IKK-α correlated positively in 92% of BCCs from BCNS patients, and in 85% of sporadic BCCs. Our findings suggest that down-regulation of IKK-α is required for 14-3-3σ promoter methylation and silencing in the pathogenesis of BCC. Besides, our observation that 14-3-3σ silencing is also frequently found in BCC from patients with BCNS suggests a possible link between the sonic hedgehog/patched and 14-3-3σ/IKK-α pathways.

Sonic hedgehog pathway dysregulation in skin basal-cell carcinoma of a Polish population

Sonic hedgehog (Shh) pathway impairment plays a key role in the pathogenesis of basal-cell carcinomas (BCC), the most frequent skin tumor among Caucasians. Shh, Smo, and Gli2 family proteins are necessary for adequate and controlled cell proliferation. The aim of this study was to evaluate Shh, Smo, and Smo expression in BCC skin biopsies taken from sun-exposed areas. 41 BCC skin biopsies and 22 healthy skin specimens (the control group) taken from the same areas served as material for the study. All specimens were immunohistochemically stained with monoclonal antibodies directed against the chosen proteins. Shh and Smo expression (cytoplasmic pattern) were recorded semiquantitatively using a four-grade score (0-3). Gli2 expression (nuclear pattern) was determined using an image analysis system (semiautomatic function). The immunoexpression of the Shh and Smo proteins significantly increased in the BCC group, as compared with the normal controls (for Shh, the mean intensity was 1.67 in BCC vs. 1.17 in the control group, p < 0.001; for Smo, the mean intensity was 1.46 in BCC vs. 0.99 in the control group, p < 0.001). The staining for Gli2 in the BCC group was completely negative, but indicated the presence of Gli2 in the control patients (1.15 Gli2+ cells/100 cells). Sonic hedgehog pathway dysregulation may play an important role in skin cancerogenesis leading to BCC development.

Etiology and pathogenesis of basal cell carcinoma

Abstract Basal cell carcinoma (BCC) is the most common cancer among Caucasians. It generally occurs on sun-exposed areas of the body, mostly on the head and neck (80%), trunk (15%), rarely on arms and legs. Basal cell carcinoma is a good example of a disease caused by a combination of genetic and environmental factors. Ultraviolet (UV) radiation plays a dual role in the development of BCC: it causes DNA damage and immunosuppression. UVA and UVB rays damage the DNA via various mechanisms. UVB radiation directly damages DNA within skin cells, causing cytosine → thymine mutations at dipyrimidine sites, whereas UVA radiation is 10.000 times less mutagenic, but it is significantly more present in the natural UV radiation. Also, UVA photons have lower energy than UVB photons and do not induce mutations. UV radiation exerts immune suppression by decreasing the antigen presenting cells ability and by producing immunosuppressive cytokines, such as interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α). Mediators of UV-induced immunosuppression are DNA and cis-urocanic acid. Several studies showed a significant association between the development of BCC and sun-exposure during childhood and adolescence, and a strong relation with family history of skin cancer. Exposure to ionizing radiation increases the risk of nonmelanoma skin cancers by three times, while the risk is proportional to the radiation dose. Chemical carcinogens, such as arsenic, tar, psoralen, and pesticides, increase risks for nonmelanoma skin cancers, predominantly for squamous cell carcinoma (SCC). Regarding genetic predisposition, there is glutathione S-transferase (GST) as an important part of cellular defense against endogenous and exogenous chemicals. Several polymorphisms in GST family members have been associated with impaired detoxification, thus influencing the risk for some cancers, including nonmelanoma skin cancers. Cytochrome P450 enzymes are involved in detoxification of photosensitizing agents, and thus involved in BCC carcinogenesis. PTCH is a tumor suppressor gene first identified in patients with Gorlin syndrome. Abnormal activation of this gene and its pathways result in various types of tumorigenesis. BCC is associated with homozygous PTCH gene deletion. With regard to acquired genetic mutations, it was found that aggressive BCCs are significantly associated with increased p53 protein expression, probably representing the mutated form, although that assertion could not be established with certainty. Considering the apparently limited contribution of DNA damage and chromosome instability to the expression of BCC phenotype, the relevance of p53 mutations for BCC growth remains to be demonstrated. Data on the role of Bcl-2 gene family in the development of BCC are scarce. It is unclear whether Bcl-2 has a functional role in the development of BCC, or it only indicates the level of gene expression in tumor stem cells. Activation of Ras gene may play an important role during early stages in the development of nonmelanoma skin cancers, and it is often found on UV-exposed skin in BCC, actinic keratosis and SCC. Concerning immunologic factors, studies have shown that tumor necrosis factor-α (TNF-α) is the critical mast cell product involved in ultraviolet-induced immunosuppression: mast cells contain high quantities of TNF-α which is released after activation; the level of TNF-α is increased in the skin exposed to UV radiation disrupting the morphology and function of Langerhans cells, the principal antigen-presenting cells of the skin. An animal study suggests that the degree of susceptibility to ultraviolet-B-induced local immunosuppression depends on TNF-α level within the epidermis after UVB. It has been established that mast cell-derived histamine stimulates prostaglandin E2 (PGE2) production from keratinocytes. PGE2 alters the cytokine balance in favor of the immunosuppressive interleukin-10 (IL-10) against the immunostimulatory IL-12; histamine also increases suppressor T-cell function by binding to the H2 receptors, which in turn release higher levels of immune suppressive cytokines including IL-10 and induce apoptosis of antigen-presenting cells. All this results in a shift of the immune response from T helper 1 (Th1) cytokine profile to T helper 2 (Th2) cytokine profile, inhibiting antigen-presenting cells to induce antitumor activity.

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC.

Basal Cell Carcinoma Presenting as a Hypertrophic Scar

Basal Cell Carcinoma Presenting as a Hypertrophic Scar

Cdc42 is involved in basal cell carcinoma carcinogenesis

Basal cell carcinoma (BCC) is the most common type of skin cancer in older persons and is a rapidly rising incidence. E-cadherin-mediated cell-cell adhesion activates Cdc42, a Rho GTPase essential for cell polarity in numerous settings. No study has yet addressed a biological significance of Cdc42 alterations in BCC pathogenesis. Our aim was to investigate E-cadherin-dependent cell-cell contacts and Cdc42 activity in BCC formation. We evaluated E-cadherin and Cdc42 expression by immunohistochemistry and Western blot analysis in samples of 15 normal skin (NS) and 30 BCC (10 superficial, 9 nodular and 11 infiltrative subtypes). Low E-cadherin and high Cdc42 immunohistochemical expression were found in BCC samples compared with NS. E-cadherin staining was significantly reduced in infiltrative BCC compared with superficial and nodular. A significantly greater Cdc42 expression was observed in BCC compared with NS; moreover, superficial BCC had a significantly lower Cdc42 expression in respect to the other subtypes. Western blot analysis confirmed the significantly decreased E-cadherin expression in infiltrative BCC as well as Cdc42 reduction in superficial BCC in respect to the other subtypes. In BCC the increased Cdc42 in association with reduced E-cadherin might contribute to the disruption of adhesion mechanisms and to the loss of cell polarity, thus explaining a mechanism by which cancer cells can escape from the control of adjacent normal keratinocytes. Our study also showed that Cdc42 and E-cadherin expression differed according to aggressive behaviour of BCC subtypes and suggested important functions of these molecules in regulating tumour demarcation and progression.

Vismodegib: A smoothened inhibitor for the treatment of advanced basal cell carcinoma

Incidence of basal cell carcinoma (BCC), the most common skin cancer in humans, is rising. Surgery is the mainstay of treatment but there is no standard of care for locally advanced or metastatic disease. Hedgehog signaling proteins are critical for cell growth and differentiation during embryogenesis; Hh pathway is silenced in adults. Dysregulated or aberrant Hh signaling has been implicated in the pathogenesis of BCC. This hyperactive pathway can be inhibited by use of smoothened inhibitors such as vismodegib. Food and drug administration approved this oral, once-daily medication in 2012 to treat adults with metastatic BCC or locally advanced, recurrent BCC after surgery and also for patients with locally advanced BCC who are not candidates for surgery or radiation treatment. Clinical studies have shown it to be highly efficacious and the most common adverse effects include, muscle spasms, alopecia and dysgeusia. Use of targeted biologic modifiers, exemplified by Hh directed therapeutics offer a new hope to patients with high-surgical morbidity or inoperable tumors.

A Hyperpigmented Perianal Nodule

Basal cell carcinoma (BCC) is the most common cutaneous malignancy. Ultraviolet light is an important risk factor for the pathogenesis of BCCs; the vast majority are found in sun-exposed areas. BCCs occurring in the perianal or genital regions are seldom seen. Less than 1% of all BCCs occur at these sites. Etiologic factors other than solar exposure must be taken into account for such cases. We report a rare case of BCC that was initially detected during a routine colonoscopy.

Molecular signatures of basal cell carcinoma susceptibility and pathogenesis: A genomic approach

Gene expression profiling can be useful for phenotypic classification, investigation of functional pathways, and to facilitate the search for disease risk genes through the integration of transcriptional data with available genomic information. To enhance our understanding of the genetic and molecular basis of basal cell carcinoma (BCC) we performed global gene expression analysis to generate a disease-associated transcriptional profile. A gene signature composed of 331 differentially expressed genes (DEGs) was generated from comparing 4 lesional and 4 site-matched control samples using Affymetrix Human Genome U95A microarrays. Hierarchical clustering based on the obtained gene signature separated the samples into their corresponding phenotype. Pathway analysis identified several significantly overrepresented pathways including PPAR-γ signaling, TGF-β signaling and lipid metabolism, as well as confirmed the importance of SHH and p53 in the pathogenesis of BCC. Comparison of our microarray data with previous microarray studies revealed 13 DEGs overlapping in 3 studies. Several of these overlapping genes function in lipid metabolism or are components of the extracellular matrix, suggesting the importance of these and related pathways in BCC pathogenesis. BCC-associated DEGs were mapped to previously reported BCC susceptibility loci including 1p36, 1q42, 5p13.3, 5p15 and 12q11-13. Our analysis also revealed transcriptional 'hot spots' on chromosome 5 which help to confirm (5p13 and 5p15) and suggest novel (5q11.2-14.3, 5q22.1-23.3 and 5q31-35.3) disease susceptibility loci/regions. Integrating microarray analyses with reported genetic information helps to confirm and suggest novel disease susceptibility loci/regions. Identification of these specific genomic and/or transcriptional targets may lead to novel diagnostic and therapeutic modalities.

1112PD - Efficacy and Safety of the Hedgehog Pathway Inhibitor Vismodegib in Patients with Advanced Basal Cell Carcinoma (BCC): 12-Month Erivance BCC Study Update

ABSTRACT Background Vismodegib (Erivedge™, GDC-0449) is a first-in-class small-molecule inhibitor of the Hedgehog signaling pathway, which is implicated in the pathogenesis of BCC. ERIVANCE BCC is the pivotal trial of vismodegib for treatment of locally advanced (laBCC) and metastatic BCC (mBCC) patients (pts) for whom there are no other effective therapies. The study met its primary endpoint of overall response rate by independent review (Dirix, ESMO 2011 LBA#1). On behalf of the ERIVANCE BCC investigators, we present the previously unreported updated investigator-assessed (I-A) efficacy and safety endpoints as of Nov 28, 2011 (additional 12 months of follow-up). Methods In this multicenter, nonrandomized 2-cohort study, pts with histologically confirmed laBCC (deemed inoperable or for whom surgery would be significantly disfiguring) or mBCC with RECIST-measurable disease, received 150 mg oral vismodegib daily. Results 104 pts (71 laBCC/33 mBCC) enrolled at 31 global sites. I-A efficacy endpoints were: Nov 26, 2010 Data Cut Nov 28, 2011 Data Cut Parameter mBCC (n = 33) laBCC (n = 63) mBCC (n = 33) laBCC (n = 63) Overall Response Rate (ORR), n (%) [95% CI] 15 (45.5) [28.1–62.2] 38 (60.3) [47.2–71.7] 16 (48.5) [30.8–66.2] 38 (60.3) [47.2–71.7] Median Duration of Response (DOR), months [95% CI] (n = 15) 12.9 [5.6–12.9] (n = 38) 7.6 [7.4–NE] (n = 16) 14.7 [5.6–NE] (n = 38) NE [9.0–NE] Median Progression-free Survival (PFS), months [95% CI] 9.2 [7.4–NE] 11.3 [9.5–16.8] 9.3 [7.4–16.6] 12.9 [10.2–NE] Median Overall Survival (OS), months [95% CI] NA NA 24.1 [14.3–NE] NE [NE–NE] With a median follow-up of 22.3 months, 1- and 2-year survival rates were 78% (95% CI 63.6–92.4%) and 60% (95% CI 42.6–78.1%), for mBCC and 93.1% (95% CI 86.6–99.6%) and 85% (95% CI 75.6–94.7%), for laBCC. Adverse events (AEs) in >30% of pts were muscle spasms, alopecia, dysgeusia, weight decrease, fatigue, nausea, and amenorrhea (in 2/6 female nonmenopausal pts). Serious AEs were reported in 33 pts (32%), compared with 26 (25%) in Nov 2010. Conclusions This 12-month update of I-A efficacy and safety data from the ERIVANCE BCC study confirms the significant clinical benefit of vismodegib in laBCC and mBCC reported at primary analysis. Median DOR and PFS increased numerically with further follow-up. The AE profile was consistent with the prior data cut. Following approval of vismodegib by the FDA, these data further support vismodegib as an effective treatment option for pts with advanced BCC. Disclosure A. Sekulic: Speaker bureau: Genentech/Roche. M.R. Migden: Advisory board: Genentech. A. Oro: Grant: Genentech, Novartis, Infinity. K. Lewis: Grant: Genentech Consulting fee/honoria: Genentech. J. Hou: Employee: Genentech Shareholder: Genentech. H. Yue: Employee: Genentech Shareholder: Genentech. A. Hauschild: Consult/honoraria:Roche, AZ, Biovex, BMS, Boehringer-Ingelheim, Celgene, Eisai, GSK, IGEA, Merck/MSD, Novartis,SOBI Reviews:Roche Spker bureau:Roche, AZ, Biovex, BMS, Boehringer-Ingelheim, Celgene, Eisai, GSK, IGEA, Merck/MSD, Novartis,SOBI. All other authors have declared no conflicts of interest.

Expression of microRNAs in basal cell carcinoma

Perturbations in the expression profiles of microRNAs (miRNAs) have been reported for a variety of different cancers. Differentially expressed miRNAs have not been systematically evaluated in basal cell carcinoma (BCC) of the skin. To initiate a microarray-based miRNA profiling study to identify specific miRNA candidates that are differentially expressed in BCC. Patients with BCC (n = 7) were included in this study. Punch biopsies were harvested from the tumour centre (lesional, n = 7) and from adjacent nonlesional skin (intraindividual control, n = 7). Microarray-based miRNA expression profiles were obtained on an Agilent platform using miRBase 16 screening for 1205 Homo sapiens (hsa)-miRNA candidates. To validate the microarray data, the expression of seven dysregulated miRNAs was measured by TaqMan quantitative real-time reverse transcription polymerase chain reaction. We identified 16 significantly upregulated (hsa-miR-17, hsa-miR-18a, hsa-miR-18b, hsa-miR-19b, hsa-miR-19b-1*, hsa-miR-93, hsa-miR-106b, hsa-miR-125a-5p, hsa-miR-130a, hsa-miR-181c, hsa-miR-181c*, hsa-miR-181d, hsa-miR-182, hsa-miR-455-3p, hsa-miR-455-5p and hsa-miR-542-5p) and 10 significantly downregulated (hsa-miR-29c, hsa-miR-29c*, hsa-miR-139-5p, hsa-miR-140-3p, hsa-miR-145, hsa-miR-378, hsa-miR-572, hsa-miR-638, hsa-miR-2861 and hsa-miR-3196) miRNAs in BCC compared with nonlesional skin. Data mining revealed connections to many tumour-promoting pathways, such as the Hedgehog and the mitogen-activated protein kinase/extracellular signal-regulated kinase signalling cascades. This study identified several miRNA candidates that may play a role in the molecular pathogenesis of BCC.

Investigational agents in metastatic basal cell carcinoma: focus on vismodegib.

Vismodegib (GDC-0449, 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, Erivedge™) is a novel first-in-human, first-in class, orally bio-available Hedgehog pathway signaling inhibitor of the G-protein coupled receptor-like protein smoothened (SMO) which was approved in the United States on January 2012. This signaling pathway is involved in the carcinogenesis of several types of tumor, as exemplified by basal cell carcinoma. This review focuses on the role of the Hedgehog pathway in the pathogenesis of basal cell carcinoma, the pharmacology and the clinical activity of vismodegib, as well as a brief summary of investigational agents in development targeting this pathway.

Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma

BackgroundAlterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.MethodsIn this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma.ResultsIn 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted.ConclusionsVismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.)

Metastatic basal cell carcinoma in the era of hedgehog signaling pathway inhibitors

Inhibition of the hedgehog signaling pathway (HHSP) for the treatment of locally advanced basal cell carcinoma (BCC) and metastatic BCC (mBCC) has produced promising results. Typically, mBCC is not taken into consideration during the workup of a patient with multifocal metastatic disease who has a history of BCC. The objective of the current review, in which the authors evaluated the time from the first BCC diagnosis to metastasis, location of disease, and radiographic features, was to contribute to the general knowledge and awareness among providers, patients, and support groups about mBCC and to provide an outlook for the future of treatments for mBCC. A literature review on mBCC and a review of records from patients with mBCC who presented to Virginia G. Piper Cancer Center Clinical Trials (an oncology clinical trials center) were conducted. The clinical and radiographic findings of 22 patients with mBCC who were evaluated at that center from the initiation of smoothened (SMO) antagonist trials were analyzed along with a review of BCC epidemiology and pathogenesis, the HHSP, and current and future treatments for this rare presentation of the most common malignancy. The results indicated that, in the last 5 years, there has been a plethora of new agents targeting SMO, a key component of the HHSP that, for the majority of patients with mBCC, may be a good match for targeting tumor genetic vulnerability. Like with other targeted therapy for uncommon malignancies, such as chronic myelogenous leukemia and gastrointestinal stromal tumors, the authors anticipate that there will be clinical development of next-generation HHSP inhibitors to combat mBCCs that are nonresponsive to or progress on current SMO antagonists.