Andreas Pinter

Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: Results from the CLEAR study

Background: Secukinumab demonstrated superior efficacy to ustekinumab at week 4 and week 16 of the CLEAR study, with comparable safety, in subjects with moderate‐to‐severe plaque psoriasis. Objective: To compare the efficacy and safety of secukinumab and ustekinumab use over 52 weeks. Methods: Analysis of 52‐week data from CLEAR, a randomized, double‐blind, phase 3b study. Results: Among 676 randomized subjects, secukinumab demonstrated superiority to ustekinumab at week 52 in the proportion of subjects with ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) (76% vs 61% [P < .0001]); PASI 100 responses were 46% versus 36% (P = .0103) and Investigators Global Assessment responses of clear/almost clear skin were 80% versus 65% (P < .0001). Subjects on secukinumab reported greater reductions in psoriasis‐related pain, itching, and scaling, and greater improvement across all quality‐of‐life measures evaluated (Dermatology Life Quality Index [DLQI], EuroQoL 5‐Dimension Health Questionnaire, Work Productivity and Activity Impairment Questionnaire‐Psoriasis, and Health Assessment Questionnaire‐Disability Index). At week 52, 72% of subjects on secukinumab versus 59% on ustekinumab (P = .0008) reported no impact of skin disease on their lives (DLQI 0/1 response). Safety and tolerability was comparable. Limitations: There was no placebo arm. Conclusion: In this head‐to‐head, double‐blind study, secukinumab demonstrated sustained superior efficacy in comparison with ustekinumab in clearing skin through week 52, greater improvement in quality of life, and a favorable and comparable safety profile.

Simultaneous blockade of VEGFR-1 and VEGFR-2 activation is necessary to efficiently inhibit experimental melanoma growth and metastasis formation

Metastasis continues to be the major cause of morbidity and mortality in malignant melanoma. In our study, we explored whether inhibition of VEGFR‐1 or VEGFR‐2 signaling conveys distinct suppressive effects on B16 melanoma subcutaneous growth and metastasis formation. The inhibition of VEGFR‐1 or ‐2 alone had no significant influence on both melanoma growth and metastasis formation. In contrast, simultaneous blockade of VEGFR‐1 and ‐2 signaling strongly suppressed progression in both B16 tumor models. There was no expression of VEGFR‐1 or ‐2 detectable on the B16 cells used, excluding the melanoma cells as direct therapeutic targets. Analyzing the contribution of progenitor‐like cells during melanoma metastasis formation, we observed an enhanced proliferation and mobilization of VEGFR‐1+ myeloid and VEGFR‐2+ endothelial cells with progenitor potential by the induction of melanoma lung metastasis, which was not influenced by interference with VEGFR signaling. These results indicate that the antimetastatic effects exerted by combined inhibition of VEGFR‐1 and ‐2 signaling were mediated via targeting cell populations other than progenitors only. Sole inhibition of VEGFR‐1 signaling led to a strong reduction of the CD45‐positive inflammatory infiltrate in the tumor tissue. However, the formation of lung metastasis was not affected, indicating that inhibition of the inflammatory response was not sufficient to efficiently block B16 melanoma metastasis development. Taken together, our data suggest that in the utilized B16 tumor models the blockade of both the inflammatory and the VEGFR‐2‐dependent angiogenic response are necessary to effectively inhibit solid tumor growth and formation of lung metastasis by B16 melanoma cells.

Lichen planus of nails - successful treatment with Alitretinoin.

Lichen planus (LP) is one of the most common inflammatory skin disorders, with a prevalence of 0.5 %. Along with the typical pattern of involvement of the skin and mucous membranes, up to 10 % of patients also have nail involvement which may be painful and stigmatizing and can lead to an impaired quality of life. The severest form of disease, in which the disease affects all 20 fingernails and toenails, is known as twentynail dystrophy.We describe the use of alitretinoin to successfully treat LP with nail involvement which we believe may present a viable new treatment option for treatment. A 43-year-old man had a 15-months history of skin and nail changes. Despite repeated failures to detect fungi, various topical and systemic antifungal therapies had been administered unsuccessfully over a period of 12 months. Distal onycholysis, sometimes severe, was observed on all fingernails and toenails as was chromonychia with yellow-brown discoloration and moderately severe longitudinal striation; a few nails also exhibited dystrophy (Figure 1a, b). There were also solitary, irregularly-bordered, slightly scaly and occasionally itching confluent papules on the lateral aspects of both shins. The mucous membranes appeared normal. The results of a skin biopsy were consistent with LP; a nail biopsy was refused. On the basis of the clinical appearance and the newly identified LP, we diagnosed twenty-nail dystrophy a ssociated with LP. Treatment with oral alitretinoin 30 mg daily was begun. Laboratory tests were performed to monitor transaminase and creatinine levels, blood count, and blood lipids (on an empty stomach) before and during therapy. Treatment lasted for a total of 24 weeks. The retinoid was well tolerated, both subjectively and on the basis of laboratory chemical test results. Within 6 weeks, therapy had led to complete healing of cutaneous symptoms. The nail changes also began to resolve after beginning treatment, with the affected portion of the nail moving distally as new nail growth occurred. After 24 weeks, all nails were completely healed (Figure 1c, d). Little is known about the etiopathology of LP. On possible cause is a T-cell mediated autoimmune response to basal keratinocytes; triggers include viral, hormonal, medication-related, and physical factors [1]. Nail involvement occurs in 1–10 % of patients with LP [2]. In patients with nail changes affecting multiple nails, the differential diagnosis includes onychomycosis, nail psoriasis, yellow nail syndrome, self-induced onychotillomania, Beau-Reil cross furrows due to severe infection or after use of certain medications, as well as Darier disease [3]. Lichen planus of nails – successful treatment with Alitretinoin

Histone deacetylase inhibitors interfere with angiogenesis by decreasing endothelial VEGFR-2 protein half-life in part via a VE-cadherin-dependent mechanism

Recent evidence suggests that histone deacetylase inhibitors (HDACi) may mediate part of their antitumor effects by interfering with tumor angiogenesis. As signalling via the vascular endothelial growth factor receptor‐2 (VEGFR‐2) pathway is critical for angiogenic responses during tumor progression, we explored whether established antitumor effects of HDACi are partly mediated through diminished endothelial VEGFR‐2 expression. We therefore examined the potential impact of three different HDACi, trichostatin A (TSA), sodium butyrate (But) and valproic acid (VPA), on VEGFR‐2 protein expression. TSA, VPA and But significantly inhibit VEGFR‐2 protein expression in endothelial cells. Pertinent to these data, VEGFR‐2 protein half‐life is shown to be decreased in response to HDACi. Recently, it could be demonstrated that expression of VE‐cadherin influences VEGFR‐2 protein half‐life. In our experiments, VEGFR‐2 downregulation was accompanied by HDACi‐induced VE‐cadherin suppression. Interestingly, siRNA‐mediated knockdown of VE‐cadherin led to a pronounced loss of VEGFR‐2 expression on the protein as well as on the mRNA level, implicating that VE‐cadherin not only influences VEGFR‐2 protein half‐life but also the transcriptional level. To further distinguish which of the eight different histone deacetylases are responsible for the regulation of VEGFR‐2 expression, specific HDAC genes were silenced by transfecting respective siRNAs. These studies revealed that HDACs 1, 4, 5 and 6 are preferentially involved in VEGFR‐2 expression. Therefore, these results provide an explanation for the anti‐angiogenic action of HDAC inhibitors via a VE‐cadherin, HDAC 1 and HDACs 4–6‐mediated suppression of VEGFR‐2 expression and might be of importance in the development of new anti‐angiogenic drugs.

Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest

Different pathologies, such as lymphoedema, cancer or psoriasis, are associated with abnormal lymphatic vessel formation. Therefore, influencing lymphangiogenesis is an interesting target. Recent evidence suggests that dimethylfumarate (DMF), an antipsoriatic agent, might have antitumorigenic and antilymphangiogenic properties. To prove this assumption, we performed proliferation and functional assays with primary human dermal lymphendothelial cells (DLEC). We could demonstrated that DMF suppresses DLEC proliferation and formation of capillary‐like structures. Underlying apoptotic mechanisms could be ruled out. Cell cycle analysis demonstrated a pronounced G1‐arrest. Further evaluations revealed increases in p21 expression. In addition, DMF suppressed Cyclin D1 and Cyclin A expression in a concentration‐dependent manner. p21 knockdown experiments demonstrated a p21‐dependent mechanism of regulation. Further analysis showed an increased p21 mRNA expression after DMF treatment. This transcriptional regulation was enforced by post‐transcriptional and post‐translational mechanisms. In addition, we could demonstrate that the combination of a proteasomal inhibitor and DMF superinduced the p21 expression. Hence, DMF is a new antilymphangiogenic compound and might be used in various illnesses associated with increased lymphangiogenesis.

The histone deacetylase inhibitor trichostatin a decreases lymphangiogenesis by inducing apoptosis and cell cycle arrest via p21-dependent pathways

BackgroundThe formation of new lymphatic vessels provides an additional route for tumour cells to metastasize. Therefore, inhibiting lymphangiogenesis represents an interesting target in cancer therapy. First evidence suggests that histone deacetylase inhibitors (HDACi) may mediate part of their antitumor effects by interfering with lymphangiogenesis. However, the underlying mechanisms of HDACi induced anti-lymphangiogenic properties are not fully investigated so far and in part remain unknown.MethodsHuman lymphatic endothelial cells (LEC) were cultured in vitro and treated with or without HDACi. Effects of HDACi on proliferation and cell cycle progress were analysed by BrdU assay and flow cytometry. Apoptosis was measured by quantifying mono- and oligonucleosomes in the cytoplasmic fraction of cell lysates. In vitro lymphangiogenesis was investigated using the Matrigel short term lymphangiogenesis assay. The effects of TSA on cell cycle regulatory proteins and apoptosis-related proteins were examined by western blotting, immunofluorescence staining and semi-quantitative RT-PCR. Protein- and mRNA half-life of p21 were analysed by western blotting and quantitative RT-PCR. The activity of the p21 promoter was determined using a dual luciferase assay and DNA-binding activity of Sp1/3 was investigated using EMSA. Furthermore, siRNA assays were performed to analyse the role of p21 and p53 on TSA-mediated anti-lymphangiogenic effects.ResultsWe found that HDACi inhibited cell proliferation and that the pan-HDACi TSA induced G0/G1 arrest in LEC. Cell cycle arrest was accompanied by up-regulation of p21, p27 and p53. Additionally, we observed that p21 protein accumulated in cellular nuclei after treatment with TSA. Moreover, we found that p21 mRNA was significantly up-regulated by TSA, while the protein and mRNA half-life remained largely unaffected. The promoter activity of p21 was enhanced by TSA indicating a transcriptional mechanism. Subsequent EMSA analyses showed increased constitutive Sp1/3-dependent DNA binding in response to HDACi. We demonstrated that p53 was not required for TSA induced p21 expression and growth inhibition of LECs. Interestingly, siRNA-mediated p21 depletion almost completely reversed the anti-proliferative effects of TSA in LEC. In addition, TSA induced apoptosis by cytochrome c release contributed to activating caspases-9, −7 and −3 and downregulating the anti-apoptotic proteins cIAP-1 and −2.ConclusionsIn conclusion, we demonstrate that TSA - a pan-HDACi - has distinct anti-lymphangiogenic effects in primary human lymphatic endothelial cells by activating intrinsic apoptotic pathway and cell cycle arrest via p21-dependent pathways.