Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment

BACKGROUND: In melanoma, several signalling pathways are constitutively activated. Among them, the RAS/RAF/MEK/ERK (MAPK) and PI3K/AKT (AKT) signalling pathways are activated through multiple mechanisms and appear to play a major role in melanoma development and progression. OBJECTIVES: In this study, we examined whether targeting the MAPK and/or AKT signalling pathways would have therapeutic effects against melanoma. METHODS: Using a panel of pharmacological inhibitors (BAY 43-9006, PD98059, U0126, wortmannin, LY294002) we inhibited the MAPK and AKT signalling pathways at different levels and evaluated the effects on growth, survival and invasion of melanoma cells in monolayer and organotypic skin culture. RESULTS: Antiproliferative and proapoptotic effects of inhibitors alone in monolayer culture were disappointing and varied among the different cell lines. In contrast, combined targeting of the MAPK and AKT signalling pathways significantly inhibited growth and enhanced apoptosis in monolayer culture. To verify our data in a more physiological context we incorporated melanoma cells into regenerated human skin mimicking the microenvironment of human melanoma. Combinations of MAPK and AKT inhibitors completely suppressed invasive tumour growth of melanoma cells in regenerated human skin. CONCLUSIONS: Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations.     

黑素瘤的自噬靶向治疗

皮肤恶性黑素瘤是一种起源于黑素细胞且恶性程度很高的肿瘤,对传统的放疗化疗均不敏感.大部分化疗药物是通过诱导凋亡发挥细胞毒作用,但对癌细胞的作用是不足的,因此,人们尝试调控细胞活力,进行其他途径的靶向治疗.虽然自噬对癌症具有促进和抑制的双重作用,但利用自噬进行癌症治疗具有广泛的应用前景.概述自噬在黑素瘤的化疗和免疫疗法中的作用,以期对皮肤恶性黑素瘤的临床诊治提供帮助.     

靶向JAK-STAT信号通路治疗银屑病的研究进展

银屑病的发生与Janus激酶(JAK)-信号转导及转录激活因子(STAT)通路密切相关, 白细胞介素(IL)-23、IL-22、γ干扰素等多种细胞因子均可通过该通路传递信号, 从而促进银屑病中角质形成细胞增殖及异常分化、炎症细胞浸润等病理过程, 提示靶向该通路是治疗银屑病的新策略。近年来, 小分子JAK抑制剂治疗银屑病显示出较好的疗效和安全性, 而靶向STAT的药物正在开发阶段, 为银屑病的治疗提供了更多选择。该文综述靶向JAK-STAT信号通路治疗银屑病的研究进展。     

Interstitial granulomatous dermatitis and granulomatous arteritis in the setting of PD-1 inhibitor therapy for metastatic melanoma

Checkpoint inhibition has become an important target in the management of malignant melanoma. As anti-CTLA4 inhibitors and anti-PD1 antibodies are increasingly utilized, reports of immune-related adverse events (IRAEs) are becoming more frequent. Common noted cutaneous IRAEs are morbilliform, lichenoid, bullous, granulomatous, psoriasiform, and eczematous eruptions. We report a case of interstitial granulomatous dermatitis and granulomatous arteritis in the setting of nivolumab (anti-PD1) monotherapy for metastatic melanoma. There are many different causes for granulomatous vasculitis, such as herpes virus infection, lymphoproliferative disorders, systemic vasculitis, and inflammatory bowel disease. This report adds to the growing literature on granulomatous IRAEs due to checkpoint inhibition.     

Topical sodium metabisulfite for the treatment of calcinosis cutis: a promising new therapy

Calcinosis cutis is a chronic calcium‐mediated disease that causes significant morbidity. Multiple treatments have been tried, with varying results; indeed, to date, no standard treatment has been generally accepted. Sodium metabisulfite is an inorganic compound that, when it reacts with oxygen, becomes sodium sulfate, a metabolite of sodium thiosulfate that has a similar ability to inhibit calcium oxalate agglomeration. Four women diagnosed with calcinosis cutis, secondary to dermatomyositis, systemic sclerosis and radiodermatitis after breast cancer, were evaluated for their response to topical 25% sodium metabisulfite. In all patients a decrease in lesion size, erythema and pain from injuries was shown, with complete resolution of the associated ulcers. One patient had a complete response. None experienced adverse effects. Topical sodium metabisulfite is a promising emerging therapy that should be considered as a valid alternative treatment in calcinosis cutis. Randomized prospective studies are required to evaluate its true efficacy.     

Sunscreens and melanoma: the future looks bright

BACKGROUND: Meta-analyses of observational case-control studies have demonstrated no association between sunscreen use and the development of malignant melanoma. OBJECTIVES: To examine whether this observation is to be expected given the period during which the case-control studies were conducted, the sunscreens prevalent at that time, and how sunscreen is used and applied in practice. To predict whether modern sunscreens are likely to be effective as a preventative agent in melanoma. METHODS: The protection against solar ultraviolet radiation delivered by sunscreens available prior to the early 1990s (when the data used in most published case-control studies were collected) was estimated by combining their absorption properties with the amount applied in a way reflecting common usage. Similar estimates were made for the protection offered by modern sunscreens. RESULTS: It is not surprising that case-control studies have failed to find any association between sunscreen use and the risk of melanoma when consideration is given to the sunscreens in common usage at the time and the way in which sunscreen is applied in practice. Modern high Sun Protection Factor, broad-spectrum sunscreens, on the other hand, can be expected to be an effective measure in helping to prevent melanoma compared with sunscreens typical of those used 10-20 years ago. CONCLUSIONS: It is reasonable to suppose that the improvement in performance of modern sunscreens will lead to a worthwhile benefit as a preventative agent against melanoma, although these benefits may not be seen for several decades.     

In situ photoimmunotherapy: a tumour-directed treatment for melanoma

We report a new immunological treatment for advanced cutaneous melanoma which combines laser stimulation with topical application of a toll-like receptor agonist. This treatment, in situ photoimmunotherapy (ISPI), provides an alternative to traditional therapies for melanoma patients with cutaneous metastases. A 6-week cycle of ISPI is carried out on cutaneous metastases located in a designated 20 x 20 cm treatment area: 2 weeks of pretreatment with twice-daily topical applications of imiquimod (5% cream under plastic occlusion), with a laser treatment session at week 2 and again at week 4. Topical imiquimod is continued for the entire 6-week cycle. Two patients with late-stage melanoma were treated with ISPI. Patient 1 had the primary tumour and local metastases on the left arm, as well as metastatic tumours in the lungs [American Joint Committee on Cancer (AJCC) stage IV]. Patient 2 had a head and neck melanoma with multiple local metastases (AJCC stage IIIC), which had failed repeated attempts at surgical resection and high-dose radiation therapy. Patient 1 is now free of all clinically detectable tumours (including the lung metastases) >20 months after the first treatment cycle. Patient 2 has been free of any clinical evidence of the tumour for over 6 months. These two cases demonstrate that ISPI can clear local tumour and trigger beneficial systemic responses, with a side-effect profile that compares favourably with other treatments for advanced melanoma.     

Synergistic inhibition of cell proliferation by combined targeting with kinase inhibitors and dietary xanthone is a promising strategy for melanoma treatment

α‐Mangostin is a dietary xanthone that displays various biological activities, and numerous reports have shown its efficacy in cancer prevention and inhibition. As most agents have been shown to be ineffective as single‐agent therapy for malignant melanoma (MM), the principle of targeted chemotherapy for MM is to use effective inhibitors and combination methods. In this study, we tested the cytotoxicity of several kinase inhibitors, including the glycogen synthase kinase (GSK)‐3 inhibitor CHIR99021, and rapamycin, in combination with a dietary xanthone, α‐mangostin, by screening from a kinase inhibitor library for melanogenesis in SK‐MEL‐2 MM cells, and verified these by clone formation efficiency, terminal dUTP nick end labelling, and expression of apoptosis‐related proteins. We also explored the molecular mechanisms for the apoptosis‐inducing effects reported. We found a marked synergistic effect of CHIR99021 or rapamycin in combination with α‐mangostin, which we verified through apoptosis‐related methods. These data provide a strong rationale for the use of α‐mangostin as an adjunct to GSK‐3 inhibitor or mammalian target of rapamycin inhibitor treatment. The intrinsic mechanism behind α‐mangostin might be inhibition of phosphatidylinositol 3‐kinase/AKT signalling and autophagy, and induction of reactive oxygen species generation.     

PD-1/PD-L1抑制剂治疗皮肤恶性肿瘤研究进展

近年来免疫检查点抑制剂程序性细胞死亡蛋白1及其配体1(PD-1/PD-L1)是皮肤恶性肿瘤治疗的重要靶点。本文就PD-1/PD-L1抑制剂在治疗皮肤恶性肿瘤的研究进展作一综述。     

The 308-nm excimer laser: a promising device for the treatment of childhood vitiligo

Background: Numerous modalities have been used to treat vitiligo in children. Up to now, phototherapy and topical corticosteroids are the most commonly used treatments for adult vitiligo but studies evaluating the efficacy of these treatments in the pediatric population remain insufficient. Objective: This study was a retrospective review to evaluate the efficacy and safety of 308‐nm excimer laser treatment in 30 childhood vitiligo patients. Methods: Thirty vitiligo patients with 40 vitiligo patches were evaluated after the cessation of 308‐nm excimer laser treatment. Results: Seventeen patients (56.7%) with 20 patches (50%) achieved an acceptable degree (>50%) of repigmentation at the end of the treatment, with five patches (12.5%) showing >75% of repigmentation. The treatment response showed anatomical preferences, favoring the face, neck and trunk. However, the treatment response did not correlate to the cumulative dose or duration of treatment. Side effects occurred in nine patients, but were transient and minimal. Conclusion: The results of this study shows that the 308‐nm excimer laser can be an effective and promising device for the treatment of various vitiligo types, other than generalized, in childhood.     

Cutaneous melanoma: making a clinical diagnosis, present and future

The minimum requirement for the general dermatologist for clinically assessing pigmented skin lesions is dermoscopy. In expert hands, this technique has been shown to improve both the sensitivity and specificity for the diagnosis of melanoma. This is also reflected by lower benign melanoma excision ratios and decreased excision rates. Evidence is mounting for the routine use of total body skin photography for patients with a very high risk of developing cutaneous melanoma. Both long-term (12 months) and short-term (3 months) digital dermoscopy monitoring has been shown to allow the detection of dermoscopically featureless melanoma and is central for the clinical assessment of melanocytic lesions at the Sydney Melanoma Diagnostic Center. The use of automated instruments for the diagnosis of cutaneous melanoma is still in an experimental phase, and its utility is dependent on the evidence that such instruments give a clinically useful expert second opinion. Currently, other noninvasive diagnostic techniques, such as in vivo confocal scanning laser microscopy, are reserved for clinical research settings.