The novel AKT inhibitor afuresertib suppresses human Merkel cell carcinoma MKL-1 cell growth.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin, which has an exceedingly poor prognosis. The AKT/mammalian target of rapamycin (mTOR) signalling pathway, which plays a pivotal role in the modulation of protein synthesis and cell survival, has been shown to be extremely important for Merkel cell carcinogenesis. In the current study, we found that AKT has important regulatory functions in MCC cells and that inhibition of AKT with the novel ATP-competitive AKT inhibitor, afuresertib, has widespread effects on proliferative pathways. In particular, we found that treatment of MCC cells with afuresertib led to deactivation of mTOR and glycogen synthase kinase 3 pathway proteins while increasing activation of proapoptotic pathways through the upregulation of p16 expression and phosphomodulation of the B-cell lymphoma-2-associated death promoter. Overall, afuresertib treatment led to significant and robust inhibition of MCC cell proliferation, thus raising intriguing questions regarding the potential efficacy of AKT inhibition for the future clinical management of MCC.

Polyomaviruses of the skin: integrating molecular and clinical advances in an emerging class of viruses.

BACKGROUND: Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses that express tumour antigen proteins. Fourteen species of polyomaviruses have been discovered in humans, and since the 2008 discovery of the first cutaneous polyomavirus - Merkel cell polyomavirus (MCPyV) - six more species have been detected in the skin: trichodysplasia spinulosa-associated polyomavirus (TSPyV), HPyV6, HPyV7, HPyV9, HPyV10 and HPyV13. Of these cutaneous species, only MCPyV, TSPyV, HPyV6 and HPyV7 have been definitively associated with diseases of the skin, most commonly in immunocompromised individuals. MCPyV is a predominant aetiology in Merkel cell carcinomas. TSPyV is one of the aetiological factors of trichodysplasia spinulosa. HPyV6 and HPyV7 have been recently linked to pruritic skin eruptions. The roles of HPyV9, HPyV10 and HPyV13 in pathogenesis, if any, are still unknown, but their molecular features have provided some insight into their functional biology. RESULTS: In this review, we summarize the known molecular mechanisms, clinical presentation and targeted therapies of each of the eight cutaneous HPyVs. CONCLUSIONS: We hope that heightened awareness and clinical recognition of HPyVs will lead to increased reports of HPyV-associated diseases and, consequently, a more robust understanding of how to diagnose and treat these conditions.

Efficacy of tildrakizumab for moderate-to-severe plaque psoriasis: pooled analysis of three randomized controlled trials at weeks 12 and 28.

BACKGROUND: Efficacy of tildrakizumab for plaque psoriasis was demonstrated in randomized, placebo-controlled trials. OBJECTIVE: To consolidate tildrakizumab efficacy results by pooling data. METHODS: Data (N = 2081) from tildrakizumab 100 mg, tildrakizumab 200 mg and placebo groups in three trials were pooled. RESULTS: Proportions of Psoriasis Area and Severity Index (PASI) 75 responders at week 12 were better with tildrakizumab 100 mg (62.3%) and tildrakizumab 200 mg (64.8%) vs. placebo (5.6%; P < 0.0001) and for PASI 90, PASI 100 and Physician's Global Assessment (PGA) 'clear' or 'minimal' vs. placebo (P < 0.0001). Responses increased from weeks 12 to 28. Week 12 PASI and PGA responses to tildrakizumab vs. placebo were numerically greater in patients with lower vs. higher bodyweight and were better with tildrakizumab 200 mg than tildrakizumab 100 mg for patients with higher bodyweight. Week 12 PASI 75 responses vs. placebo with tildrakizumab 100 mg were similar between patients with (55.0%) or without (56.7%) prior biologics. PASI 90, PASI 100 and PGA responses were generally higher in patients without prior biologics. Week 8 PASI 50 response predicted PASI 90 response. CONCLUSION: Pooled data confirmed the efficacy of tildrakizumab for moderate-to-severe plaque psoriasis.

Safety of tildrakizumab for moderate-to-severe plaque psoriasis: pooled analysis of three randomized controlled trials.

BACKGROUND: Short-term interleukin-23p19 inhibition by tildrakizumab improves plaque psoriasis and appears to be well tolerated. OBJECTIVES: Safety and tolerability were assessed for up to 64 weeks of tildrakizumab therapy using pooled data from three randomized controlled trials for moderate-to-severe psoriasis. METHODS: Data pools for the placebo-controlled (up to 16 weeks) and full trial periods (up to 64 weeks) were analysed (n = 2081). RESULTS: In the placebo-controlled period, frequencies of treatment-emergent adverse events (TEAEs; range 47·9-54·0%), serious TEAEs (range 1·4-2·3%), discontinuations due to AEs (range 0·6-1·9%), major adverse cardiovascular events (MACEs; range 0·0-0·1%) and severe infections (range 0·0-0·3%) were comparable between tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and etanercept. In the full trial period, exposure-adjusted rates (patients per 100 patient-years) for TEAEs, serious TEAEs and discontinuations due to AEs with tildrakizumab 100 mg and 200 mg were lower than or comparable with the placebo rates, and lower than with etanercept. Exposure-adjusted rates of MACEs (range 0·0-0·5) and severe infections (range 0·9-2·0) were comparable among groups. No TEAEs of inflammatory bowel disease or suicide were reported. Candida skin infections were infrequent at frequencies of 0·1%, 0·3%, 0·0% and 0·0% for the tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and etanercept groups, respectively, in the placebo-controlled period, and exposure-adjusted rates of 0·2, 0·7, 0·0 and 0·0, respectively, in the full trial period. Oral candidiasis was also infrequent. CONCLUSIONS: Up to 64 weeks of tildrakizumab was well tolerated, with low rates of serious TEAEs, discontinuations due to AEs, and AEs of clinical interest.

BRAF inhibitor-associated cutaneous squamous cell carcinoma: new mechanistic insight, emerging evidence for viral involvement and perspectives on clinical management.

Mutations in the BRAF proto-oncogene occur in the majority of cutaneous melanomas. The commonly detected valine (V) to glutamate (E) mutation (V600E) is known to drive melanomagenesis and has thus been the target of two highly selective chemotherapeutic agents: vemurafenib and dabrafenib. While BRAF inhibitor therapy has revolutionized the treatment of metastatic melanoma, unanticipated cutaneous toxicities, including the development of cutaneous squamous cell carcinomas (cSCCs), are frequently reported and hinder therapeutic durability. However, the mechanisms by which BRAF inhibitors induce cutaneous neoplasms are poorly understood, thus posing a challenge for specific therapies. In this review, we summarize the clinical and molecular profiles of BRAF inhibitor-associated cSCCs, with a focus on factors that may contribute to disease pathogenesis. In particular, we discuss the emerging evidence pointing towards viral involvement in BRAF inhibitor-induced cutaneous neoplasms and offer new perspectives on future therapeutic interventions. Continued clinical and mechanistic studies along this line will not only allow for better understanding of the pathogenic progression of BRAF inhibitor-induced cSCCs, but will also lead to development of new therapeutic and preventative options for patients receiving targeted cancer therapy.

Dysregulation of the MEK/ERK/MNK1 signalling cascade by middle T antigen of the trichoydsplasia spinulosa polyomavirus.

BACKGROUND: Trichodysplasia spinulosa (TS) is a disfiguring folliculocentric cutaneous disease caused by infection with the trichodysplasia spinulosa polyomavirus (TSPyV). The TSPyV genome contains splice variants encoding the middle tumour (mT) antigen, although the potential role for TSPyV mT antigen in disease development remains unknown. OBJECTIVE: The current study was designed to investigate the mechanistic properties of TSPyV mT antigen, which may further our understanding of TS pathogenesis and provide insight into potential therapies. METHODS: A lentiviral packaging system was used to create an inducible cell line expressing TSPyV mT antigen. Proteins were extracted, separated by SDS-PAGE and subjected to Western blot analysis. Co-immunoprecipitation experiments and mutational analyses were also performed to evaluate protein-protein interactions of mT antigen. RESULTS: We describe a novel mechanism of action for mT antigen that involves hyperactivation of MEK, ERK and MNK1. Our findings suggest that dysregulation of these key signalling molecules depends upon TSPyV mT antigen interaction with protein phosphatase 2A (PP2A) via intact Zn binding motifs. CONCLUSION: Given that PP2A interaction and MEK/ERK/MNK1 phosphorylation are associated with high levels of cell proliferation and inflammation, our findings provide new evidence that TSPyV mT antigen may contribute to the pro-proliferative conditions that lead to TS development.

Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease.

BACKGROUND: Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative. OBJECTIVE: The aim of this study was to report EV-causing mutations in four patients with EV and to give an overview of all described patients with EV. PATIENTS AND METHODS: We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood, and ß-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types. RESULTS: Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described patients with EV. Around 40% of patients with EV analysed for genetic alterations carried no mutation in TMC6/8. While ß-HPVs were identified in the majority of cases, α-HPVs were detected in several individuals. CONCLUSION: The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in patients with EV, but HPV-3, HPV-14 and HPV-20 were unexpectedly identified more frequently than HPV-8.

Dupilumab for Moderate-to-Severe Atopic Dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory disease affecting 2-10% of adults and up to 15-30% of children. Despite a rising prevalence, effective and safe therapeutics for patients with moderate-to-severe AD are limited due to toxicity and side effects. Dupilumab, an interleukin (IL)-4 and IL-13 antagonist that limits type 2 T helper (Th2) driven inflammatory activity, is a promising therapeutic option. In clinical trials, it has demonstrated efficacy by reducing clinical activity and symptoms, and showed improvement in the AD genomic phenotype, including a significant reduction in Th2 chemokines and reversal of key epidermal markers of AD. It also has a favorable safety profile. This review discusses the role of dupilumab in treating Th2 related inflammation, and its efficacy and safety, as demonstrated in clinical trials. Dupilumab (Dupixent®) recently gained US FDA approval for patients with moderate-to-severe AD, and is poised to revolutionize the management of this chronic, relapsing condition.

A Review of Brodalumab, an IL-17 Receptor Antagonist, for Moderate-to-Severe Plaque Psoriasis.

Psoriasis is a chronic immune-mediated inflammatory disease with epidermal hyperplasia that affects 2-3% of the population. Interleukin (IL)-17 signaling has a central role in its pathogenesis. Brodalumab is a monoclonal antibody that neutralizes IL-17 receptor type A. Brodalumab is highly effective in the reversal of psoriatic phenotype and gene expression patterns.

Molecular insight into the viral biology and clinical features of trichodysplasia spinulosa.

Trichodysplasia spinulosa (TS) is a disfiguring skin disease that occurs most frequently in patients receiving immunosuppressive therapies, and is thus frequently associated with organ transplantation. TS is characterized clinically by folliculocentric papular eruption, keratin spine formation and development of leonine face; and histologically by expansion of the inner root sheath epithelium and high expression of the proliferative marker Ki-67. Recent discovery of the TS-associated polyomavirus (TSPyV) and emerging studies demonstrating the role of TSPyV tumour antigens in cell proliferation pathways have opened a new corridor for research on TS. In this brief review, we summarize the clinical and histological features of TS and evaluate the current options for therapy. Furthermore, we address the viral aetiology of the disease and explore the mechanisms by which TSPyV may influence TS development and progression. As reports of TS continue to rise, clinician recognition of TS, as well as accompanying research on its underlying pathogenesis and therapeutic options, is becoming increasingly important. It is our hope that heightened clinical suspicion for TS will increase rates of diagnosis and will galvanize both molecular and clinical interest in this disease.

A Review of Ixekizumab, an Anti-Interleukin-17A Monoclonal Antibody, for Moderate-to-Severe Plaque Psoriasis.

Psoriasis is a multifactorial chronic skin disease that can have significant detrimental effects on patients' physical, mental, antibodypsychosocial wellbeing. Patients often suffer from a decreased quality of life along with numerous comorbidities. Recent advances in our understanding of the innate and adaptive immune systems have led to the identification of interleukin (IL)-17 as a key pro-inflammatory mediator in psoriasis. This knowledge has in turn led to the development of newer biologic agents that have been shown to be more effective than traditional therapies. In this article, we review phase 1-3 clinical trials of the anti-IL-17 monoclonal antibody, ixekizumab, for treatment of moderate-to-severe plaque psoriasis.

Generalized verrucosis in a patient with GATA2 deficiency.

Generalized verrucosis is a characteristic of several genetic and immunodeficiency disorders including epidermodysplasia verruciformis; warts, hypogammaglobulinaemia, infections and myelokathexis (WHIM) syndrome; warts, immunodeficiency, lymphoedema and anogenital dysplasia (WILD) syndrome; severe combined immune deficiency and HIV, among others. In recent years, it has been consistently recognized in patients with GATA2 deficiency, a novel immunodeficiency syndrome characterized by monocytopenia, B-cell and natural killer-cell lymphopenia, and a tendency to develop myeloid leukaemias and disseminated mycobacterial, human papillomavirus (HPV) and opportunistic fungal infections. Mutations in GATA2 cause haploinsufficiency and track in families as an autosomal dominant immunodeficiency. GATA2 is a transcription factor involved in early haematopoietic differentiation and lymphatic and vascular development. We describe a case of generalized verrucosis with HPV type 57 presenting in a young man with GATA2 deficiency. GATA2 deficiency is a novel dominant immunodeficiency that is often recognized later in life and should be considered in the differential diagnosis of patients with generalized verrucosis.