Exploring the role of epigenetic alterations and non-coding RNAs in melanoma pathogenesis and therapeutic strategies.

Melanoma is a rare but highly lethal type of skin cancer whose incidence is increasing globally. Melanoma is characterized by high resistance to therapy and relapse. Despite significant advances in the treatment of metastatic melanoma, many patients experience progression due to resistance mechanisms. Epigenetic changes, including alterations in chromatin remodeling, DNA methylation, histone modifications, and non-coding RNA rearrangements, contribute to neoplastic transformation, metastasis, and drug resistance in melanoma. This review summarizes current research on epigenetic mechanisms in melanoma and their therapeutic potential. Specifically, we discuss the role of histone acetylation and methylation in gene expression regulation and melanoma pathobiology, as well as the promising results of HDAC inhibitors and DNMT inhibitors in clinical trials. We also examine the dysregulation of non-coding RNA, particularly miRNAs, and their potential as targets for melanoma therapy. Finally, we highlight the challenges of epigenetic therapies, such as the complexity of epigenetic mechanisms combined with immunotherapies and the need for combination therapies to overcome drug resistance. In conclusion, epigenetic changes may be reversible, and the use of combination therapy between traditional therapies and epigenetically targeted drugs could be a viable solution to reverse the increasing number of patients who develop treatment resistance or even prevent it. While several clinical trials are underway, the complexity of these mechanisms presents a significant challenge to the development of effective therapies. Further research is needed to fully understand the role of epigenetic mechanisms in melanoma and to develop more effective and targeted therapies.

Sentinel Lymph Node Biopsy in Malignant Melanoma of the Head and Neck: A Single Center Experience.

Purpose: This study evaluated the characteristics of patients with head and neck (H&N) melanoma who underwent sentinel lymph node biopsy (SNLB) and assessed the clinical course of patients categorizing subjects according to SLNB status and melanoma location (scalp area vs. non-scalp areas). Methods: Patients undergoing SLNB for melanoma of H&N from 2015 to 2021 were prospectively characterized according to sentinel lymph node (SLN) status. SPECT/CT had been previously performed. Patients were followed until the first adverse event to evaluate progression-free survival. Results: 93 patients were enrolled. SLNB was negative in 75 patients. The median Breslow index was higher for patients with positive SLNB compared with patients with negative SLNB. In addition, the Breslow index was higher for melanoma of the scalp compared with non-scalp melanoma. The median follow-up was 24.8 months. Progression occurred at the systemic level in the 62.5% of cases. There was a significant association between positive SLNB and progression (p-value < 0.01) of disease, with lower progression-free survival for patients with melanoma of the scalp compared with those with melanoma at other anatomic sites (p-value: 0.15). Conclusions: Scalp melanomas are more aggressive than other types of H&N melanomas. Sentinel lymph node status is the strongest prognostic criterion for recurrence.

Classic and new strategies for the treatment of advanced melanoma and non-melanoma skin cancer.

Advanced melanoma and non-melanoma skin cancers (NMSCs) are burdened with a dismal prognosis. To improve the survival of these patients, studies on immunotherapy and target therapies in melanoma and NMSCs are rapidly increasing. BRAF and MEK inhibitors improve clinical outcomes, and anti-PD1 therapy demonstrates better results than chemotherapy or anti-CTLA4 therapy in terms of the survival of patients with advanced melanoma. In recent years, the combination therapy of nivolumab plus ipilimumab has gained ground in studies for its survival and response rate benefits in patients with advanced melanoma. In addition, neoadjuvant treatment for stages III and IV melanoma, either as monotherapy or combination therapy, has recently been discussed. Another promising strategy evaluated in recent studies is the triple combination of anti-PD-1/PD-L1 immunotherapy and anti-BRAF plus anti-MEK targeted therapy. On the contrary, in advanced and metastatic BCC, successful therapeutic strategies, such as vismodegib and sonidegib, are based on the inhibition of aberrant activation of the Hedgehog signaling pathway. In these patients, anti-PD-1 therapy with cemiplimab should be reserved as the second-line therapy in case of disease progression or poor response. In patients with locally advanced or metastatic SCC, who are not candidates for surgery or radiotherapy, anti-PD1 agents such as cemiplimab, pembrolizumab, and cosibelimab (CK-301) have shown significant results in terms of response rate. PD-1/PD-L1 inhibitors, such as avelumab, have also been used in Merkel carcinoma, achieving responses in half of the patients with advanced disease. The latest prospect emerging for MCC is the locoregional approach involving the injection of drugs that can stimulate the immune system. Two of the most promising molecules used in combination with immunotherapy are cavrotolimod (a Toll-like receptor 9 agonist) and a Toll-like receptor 7/8 agonist. Another area of study is cellular immunotherapy with natural killer cells stimulated with an IL-15 analog or CD4/CD8 cells stimulated with tumor neoantigens. Neoadjuvant treatment with cemiplimab in CSCCs and nivolumab in MCCs has shown promising results. Despite the successes of these new drugs, the new challenges ahead will be to select patients who will benefit from these treatments based on biomarkers and parameters of the tumor microenvironment.