Search

A series of seleno-containing polyfunctionalized compounds was synthesized exploring cyanohydrin chemistry, including α-hydroxy esters, α-hydroxy acids, 1,2-diols, and 1,2-diacetates, with yields ranging from 26 up to 99 %. The cytotoxicity of all synthesized compounds was then evaluated using a non-tumor cell line (BALB/3T3 murine fibroblasts), and those deemed non-cytotoxic had their anti-melanoma activity evaluated using B16-F10 murine melanoma cells. These assays identified two compounds with selective cytotoxic activity against the tested melanoma cell line, showing a potential anti-melanoma application., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leandro Piovan reports financial support was provided by Federal University of Parana. Leandro Piovan reports a relationship with Federal University of Parana that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Cytokines IL2 and IL12 exhibit potent anticancer activity but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability to bind and associate with tumor collagen after intratumoral injection potentiated response without toxicity in mice and was previously safe in pet dogs with sarcoma. Here, we sought to test the efficacy of this approach in dogs with advanced melanoma., Patients and Methods: This study examined 15 client-owned dogs with histologically or cytologically confirmed malignant melanoma that received a single 9-Gy fraction of radiotherapy, followed by six cycles of combined collagen-anchored IL2 and IL12 therapy every 2 weeks. Cytokine dosing followed a 3 + 3 dose escalation design, with the initial cytokine dose chosen from prior evaluation in canine sarcomas. No exclusion criteria for tumor stage or metastatic burden, age, weight, or neuter status were applied for this trial., Results: Median survival regardless of the tumor stage or dose level was 256 days, and 10/13 (76.9%) dogs that completed treatment had CT-measured tumor regression at the treated lesion. In dogs with metastatic disease, 8/13 (61.5%) had partial responses across their combined lesions, which is evidence of locoregional response. Profiling by NanoString of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy., Conclusions: Collectively, these results confirm the ability of locally administered tumor-anchored cytokines to potentiate responses at regional disease sites when combined with radiation. This evidence supports the clinical translation of this approach and highlights the utility of comparative investigation in canine cancers., (©2024 American Association for Cancer Research.)

Background: Immunotherapies for malignant melanoma are challenged by the resistance developed in a significant proportion of patients. Myeloid-derived suppressor cells (MDSC), with their ability to inhibit antitumor T-cell responses, are a major contributor to immunosuppression and resistance to immune checkpoint therapies in melanoma. Damage-associated molecular patterns S100A8, S100A9, and HMGB1, acting as toll like receptor 4 (TLR4) and receptor for advanced glycation endproducts (RAGE) ligands, are highly expressed in the tumor microenvironment and drive MDSC activation. However, the role of TLR4 and RAGE signaling in the acquisition of MDSC immunosuppressive properties remains to be better defined. Our study investigates how the signaling via TLR4 and RAGE as well as their ligands S100A9 and HMGB1, shape MDSC-mediated immunosuppression in melanoma., Methods: MDSC were isolated from the peripheral blood of patients with advanced melanoma or generated in vitro from healthy donor-derived monocytes. Monocytes were treated with S100A9 or HMGB1 for 72 hours. The immunosuppressive capacity of treated monocytes was assessed in the inhibition of T-cell proliferation assay in the presence or absence of TLR4 and RAGE inhibitors. Plasma levels of S100A8/9 and HMGB1 were quantified by ELISA. Single-cell RNA sequencing (scRNA-seq) was performed on monocytes from patients with melanoma and healthy donors., Results: We showed that exposure to S100A9 and HMGB1 converted healthy donor-derived monocytes into MDSC through TLR4 signaling. Our scRNA-seq data revealed in patient monocytes enriched inflammatory genes, including S100 and those involved in NF-κB and TLR4 signaling, and a reduced major histocompatibility complex II gene expression. Furthermore, elevated plasma S100A8/9 levels correlated with shorter progression-free survival in patients with melanoma., Conclusions: These findings highlight the critical role of TLR4 and, to a lesser extent, RAGE signaling in the conversion of monocytes into MDSC-like cells, underscore the potential of targeting S100A9 to prevent this conversion, and highlight the prognostic value of S100A8/9 as a plasma biomarker in melanoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Squalene (SQ) is a well-known antioxidant and anti-inflammatory agent that provides promising anti-aging and UV-protective roles on human skin. However, its strong hydrophobic nature, accompanied by issues such as poor solubility and limited tissue permeation, has created challenges for scientists to investigate its untapped potential in more complex conditions, including cancer progression. The present study assessed the potent anti-metastatic properties of a newly synthesized amphiphilic ethylene glycol SQ derivative (SQ-diEG) in melanoma, the most fatal skin cancer. In vitro and in vivo experiments have discovered that SQ-diEG may exert its potential on melanoma malignancy through the mitochondria-mediated caspase activation apoptotic signaling pathway. The potent anti-metastatic effect of SQ-diEG was observed in vitro using highly proliferative and aggressive melanoma cells. Administration of SQ-diEG (25 mg/kg) significantly decreased the tumor burden on the lung and inhibited the metastasis-associated proteins and gene markers in B16F10 lung colonization mice model. Furthermore, global gene profiling also revealed a promising role of SQ-diEG in tumor microenvironment. We anticipated that the amphiphilic nature of the SQ compound bearing ethylene glycol oligomers could potentially augment its ability to reach the pathology site, thus enhancing its therapeutic potential in melanoma., (© 2024. The Author(s).)

Melanoma is a skin cancer originating from melanocytes. The global incidence rate of melanoma is rapidly increasing, posing significant public health challenges. Identifying effective therapeutic agents is crucial in addressing this growing problem. Natural products have demonstrated promising anti-tumor activity. In this study, a plant flavonoid, taxifolin, was screened using Weighted Correlation Network Analysis (WGCNA) in combination with the Connectivity Map (CMAP) platform. Taxifolin was confirmed to inhibit the proliferation, migration, and invasion ability of melanoma A375 and MV-3 cells by promoting apoptosis. Additionally, it suppressed the Epithelial-Mesenchymal Transition (EMT) process of melanoma cells. Cyber pharmacological analysis revealed that taxifolin exerts its inhibitory effect on melanoma through the PI3K/AKT signaling pathway, specifically by downregulating the protein expression of p-PI3K and p-AKT. Notably, the addition of SC-79, an activator of the PI3K/AKT signaling pathway, reversed the effects of taxifolin on cell migration and apoptosis. Furthermore, in vivo experiments demonstrated that taxifolin treatment slowed tumor growth in mice without significant toxic effects. Based on these findings, taxifolin holds promise as a potential drug for melanoma treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Combination immunotherapy improves outcomes in metastatic melanoma, but the underlying mechanisms remain unclear. In this issue of Cancer Cell, Wang et al. 1 report dynamics and transcriptional states of CD8 + T cell clones over time in patients treated with anti-PD-1, anti-CTLA-4, or a combination of the two. These findings have important implications for understanding and monitoring combination immunotherapy., Competing Interests: Declaration of interests J.M.K. is a consultant for Ankyra Therapeutics; Axio Research, LLC; Boxer Capital; Bristol Myers Squibb; CytomX Therapeutics; DermTech; Engage Health Media; iOnctura; Iovance Biotherapeutics; IQVIA; Istari Oncology; Jazz Pharmaceuticals, Inc.; Lumira Capital Investment Management, Inc.; Lytix Biopharma AS; Magnolia Innovation, LLC; Merck; Natera, Inc.; Novartis Pharmaceuticals; OncoCyte Corporation; PathAI, Inc.; Pfizer, Inc.; Piper Sandler & Co.; Pyrojas Corporation; Regeneron Pharmaceuticals, Inc.; Replimune, Inc.; Scopus BioPharma, Inc.; Takeda; and Valar Labs, Inc. J.M.K. provides research trial support to Amgen, Inc.; Bristol Myers Squibb; Checkmate Pharmaceuticals; Harbour BioMed; ImmVira Pharma Co.; Immunocore, Ltd.; Iovance Biotherapeutics; Lion Biotechnologies, Inc.; Lytix Biopharma AS; Novartis Pharmaceuticals; Takeda; and Verastem, Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 + T cells and exhausted CD8 + T cell (T EX ) clones. Focused analyses of T EX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor T EX , which synergizes with anti-PD-1 to reinvigorate T EX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies., Competing Interests: Declaration of interests A.C.H. performed consulting work for Immunai and received research funding from Bristol Myers Squibb and Merck. R.S.H. has performed consulting work for Bristol Myers Squibb (exclusive of the current work). T.C.M. received honorarium for Scientific Advisory Board participation from: BMS, GigaGen, Merck, Pliant, Pfizer. G.C.K. is on the Merck Advisory Board. J.W. consulted for and have received less than $10,000 per annum from Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, and EMD Serono and received $10–$25,000 from BMS for membership on advisory boards. J.W. also holds equity in Biond, Evaxion, OncoC4, and Instil Bio, and on scientific advisory boards for CytomX, Incyte, ImCheck, Biond, Sellas, Instil Bio, OncoC4, and NexImmune and remunerated between $10,000–$50,000. In addition, J.W. is named on a patent filed by Moffitt Cancer Center on an ipilimumab biomarker and on TIL preparation and also on a PD-1 patent filed by Biodesix; J.W. receives less than $6000 in royalties. D.B., E.K., and C.S. were employed by Immunai when engaged in this project. S.G. and D.T. are employees of BMS. C.A. is a consultant for Biotherapy Partners., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF, NRAS, or CKIT targeting, has rarely been reported., Materials and Methods: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF, NRAS, or CKIT alterations and patients who received molecularly matched therapy for less than 15 days., Results: We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11, MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1, MDM2/CDK4, and CDKN2A/NRAS alterations., Conclusions: High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments., (© The Author(s) 2024. Published by Oxford University Press.)

Melanoma is a malignant skin cancer associated with high mortality rates and drug resistance, posing a significant threat to human health. The combination of chemotherapy and photodynamic therapy (PDT) represents a promising strategy to enhance antitumor efficacy through synergistic anti-cancer effects. Topical delivery of chemotherapeutic drugs and photosensitizers (PS) offers a non-invasive and safe way to treat melanoma. However, the effectiveness of these treatments is often hindered by challenges such as limited skin permeability and instability of the PS. In this study, transfersomes (TFS) were designed to facilitate transdermal delivery of the chemotherapeutic drug 5-Fluorouracil (5-FU) and the PS Imperatorin (IMP) for combined chemo-photodynamic therapy for melanoma. The cytotoxic and phototoxic effects of TFS-mediated PDT (TFS-UVA) were investigated in A375 cells and nude mice. The study also demonstrated that TFS-UVA generated intracellular ROS, induced G2/ M phase cell cycle arrest, and promoted cell apoptosis. In conclusion, this study indicated that 5-FU/ IMP-TFS serves as an effective transdermal therapeutic strategy for chemo-PDT in treating melanoma.

Neoantigen-based immunotherapy is an attractive potential treatment for previously intractable tumors. To effectively broaden the application of this approach, stringent biomarkers are crucial to identify responsive patients. ARID1A, a frequently mutated subunit of SWI/SNF chromatin remodeling complex, has been reported to determine tumor immunogenicity in some cohorts; however, mutations and deletions of ARID1A are not always linked to clinical responses to immunotherapy. In this study, we investigated immunotherapeutic responses based on ARID1A status in targeted therapy-resistant cancers. Mouse and human BRAFV600E melanomas with or without ARID1A expression were transformed into resistant to vemurafenib, an FDA-approved specific BRAFV600E inhibitor. Anti-PD-1 antibody treatment enhanced antitumor immune responses in vemurafenib-resistant ARID1A-deficient tumors but not in ARID1A-intact tumors or vemurafenib-sensitive ARID1A-deficient tumors. Neoantigens derived from accumulated somatic mutations during vemurafenib resistance were highly expressed in ARID1A-deficient tumors and promoted tumor immunogenicity. Furthermore, the newly generated neoantigens could be utilized as immunotherapeutic targets by vaccines. Finally, targeted therapy resistance-specific neoantigen in experimental human melanoma cells lacking ARID1A were validated to elicit T-cell receptor responses. Collectively, the classification of ARID1A-mutated tumors based on vemurafenib resistance as an additional indicator of immunotherapy response will enable a more accurate prediction to guide cancer treatment. Furthermore, the neoantigens that emerge with therapy resistance can be promising therapeutic targets for refractory tumors. Significance: Chemotherapy resistance promotes the acquisition of immunogenic neoantigens in ARID1A-deficient tumors that confer sensitivity to immune checkpoint blockade and can be utilized for developing antitumor vaccines, providing strategies to improve immunotherapy efficacy., (©2024 American Association for Cancer Research.)

Cutaneous melanoma is an aggressive type of skin cancer that is recognized for its high metastatic potential and the challenges it presents in its treatment. There has been increasing interest in plant extracts and their potential applications in melanoma. The present study aimed to investigate the content of individual phenolic compounds in araçá-boi extract, evaluate their antioxidant activity, and explore their effects on cell viability, migration properties, oxidative stress levels, and protein expression in the human metastatic melanoma cell line SK-MEL-28. HPLC-DAD analysis identified 11 phenolic compounds in the araçá-boi extract. Trans-cinnamic acid was the main phenolic compound identified; therefore, it was used alone to verify its contribution to antitumor activities. SK-MEL-28 melanoma cells were treated for 24 h with different concentrations of araçá-boi extract and trans-cinnamic acid (200, 400, 600, 800, and 1600 µg/mL). Both the araçá-boi extract and trans-cinnamic acid reduced cell viability, cell migration, and oxidative stress in melanoma cells. Additionally, they modulate proteins involved in apoptosis and inflammation. These findings suggest the therapeutic potential of araçá-boi extract and its phenolic compounds in the context of melanoma, especially in strategies focused on preventing metastasis. Additional studies, such as the analysis of specific signaling pathways, would be valuable in confirming and expanding these observations.

Background: Following major achievements seen with drug therapies for the treatment of advanced melanoma in the last decade, they now also have an ever-increasing role for the treatment of earlier stage disease. This review outlines the current drugs used to treat melanoma, and how general practitioners (GPs) can assist in the management of patients with melanoma and the associated toxicities with treatment., Objective: This review summarises the evolving status of melanoma care, emphasising when to refer patients to medical oncologists as part of the multidisciplinary team. It provides guidance into recognising and managing immune-related adverse events (irAEs) associated with immunotherapy, and provides insights into the future changes in clinical practice., Discussion: Drug therapies are increasingly used for the treatment of many patients with melanoma. Early referral is crucial, and clinical trials remain the best choice for most patients. Recognition and prompt management of irAEs is vital, and collaboration between GPs and oncologists is essential for best care.

Background: Melanoma is a heterogeneous cancer influenced by the plasticity of melanoma cells and their dynamic adaptations to microenvironmental cues. Melanoma cells transition between well-defined transcriptional cell states that impact treatment response and resistance., Methods: In this study, we applied single-cell RNA sequencing to interrogate the molecular features of immunotherapy-naive and immunotherapy-resistant melanoma tumours in response to ex vivo BRAF/MEK inhibitor treatment., Findings: We confirm the presence of four distinct melanoma cell states - melanocytic, transitory, neural-crest like and undifferentiated, and identify enrichment of neural crest-like and undifferentiated melanoma cells in immunotherapy-resistant tumours. Furthermore, we introduce an integrated computational approach to identify subsets of responding and nonresponding melanoma cells within the transcriptional cell states., Interpretation: Nonresponding melanoma cells are identified in all transcriptional cell states and are predisposed to BRAF/MEK inhibitor resistance due to pro-inflammatory IL6 and TNFɑ signalling. Our study provides a framework to study treatment response within distinct melanoma cell states and indicate that tumour-intrinsic pro-inflammatory signalling contributes to BRAF/MEK inhibitor resistance., Funding: This work was supported by Macquarie University, Melanoma Institute Australia, and the National Health and Medical Research Council of Australia (NHMRC; grant 2012860, 2028055)., Competing Interests: Declaration of interests JHL has received honorarium from Merck, Sharp & Dohme and AstraZeneca, received conference support from Pfizer and Merck, Sharp & Dohme, and consulting fees from Boxer Capitol. JHL is a consultant for Merck, Sharp & Dohme, Sanofi, Cancer Council and EviO. RAS has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline, IO Biotech ApS and SkylineDX B.V. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer Health Care, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IO Biotech, Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Qbiotics, Regeneron, Scancell Limited and SkylineDX B.V. GVL has received conference support from Bristol Myers Squibb and Pierre Fabre. All other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background/aim: Uveal melanoma (UM) represents a prevailing primary intraocular malignancy, with a limited median overall survival among metastatic patients, and most tumors lack RAF/RAS mutations. The pan-RAF inhibitor LY3009120 has demonstrated valuable anti-tumor effects in a wide range of RAF/RASmut and wild-type (WT) tumor models. This study aimed to evaluate the antitumor effect of LY3009120 on 92-1 UM cell line., Materials and Methods: The effect of the pan-RAF inhibitor LY3009120 on cell proliferation, metabolic activity, biomass, early and late apoptosis/necrosis, and morphology was characterized in vitro (0.1-5 μM for 48 h/72 h). Furthermore, targeted panel sequencing was used to characterize the mutational landscape of the human 92-1 UM cell line., Results: LY3009120 showed a significant concentration-dependent anti-proliferative effect on 92-1 cells. Cell proliferation and viability were significantly reduced at the lowest effective concentration of 0.5 μM (at 48 and 72 h, p<0.001). Furthermore, LY3009120 caused significant early apoptosis and late apoptosis/necrosis in 92-1 cells at 5 μM. Except for TP53, NGS showed that all 49 additional analysed genes (Oncomine myeloid panel) of 92-1 were wild-type, including BRAF, NRAS, and KRAS., Conclusion: The pan-RAF inhibitor LY3009120 demonstrated a significant anti-tumor effect on human UM cell line 92-1 independent of the molecular BRAF and RAS mutational status., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Malignant melanoma is a tumor with a poor prognosis that can metastasize distally at an early stage. Terrein, a metabolite produced by Aspergillus terreus, suppresses the expression of angiogenin, an angiogenic factor. However, the pharmacological effects of natural terrein have not been elucidated, because only a small amount of terrein can be extracted from large fungal cultures. In this study, we investigated the antineoplastic effects of terrein on human malignant melanoma cells and its underlying mechanisms., Materials and Methods: Human malignant melanoma cell lines were cultured in the presence of terrein and analyzed. Angiogenin production was evaluated using ELISA. Ribosome biosynthesis was evaluated using silver staining of the nucleolar organizer region. Intracellular signaling pathways were analyzed using western blotting. Malignant melanoma cells were transplanted subcutaneously into the backs of nude mice. The tumors were removed at 5 weeks and analyzed histopathologically., Results: Terrein inhibited angiogenin expression, proliferation, migration, invasion, and ribosome biosynthesis in malignant melanoma cells. Terrein was shown to inhibit tumor growth and angiogenesis in animal models., Conclusion: This study demonstrated that terrein has anti-tumor effects against malignant melanoma. Furthermore, chemically synthesized non-natural terrein can be mass-produced and serve as a novel potential anti-tumor drug candidate., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: The presence of tumor-infiltrating lymphocytes (TILs) in melanoma has been linked to survival. Their predictive capability for immune checkpoint inhibition (ICI) response remains uncertain. Therefore, we investigated the association between treatment response and TILs in the largest cohort to date and analyzed if this association was independent of known clinical predictors., Methods: In this multicenter cohort study, patients who received first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were identified. TILs were scored on hematoxylin and eosin (H&E) slides of primary melanoma and pre-treatment metastases using the validated TILs-WG, Clark and MIA score. The primary outcome was objective response rate (ORR), with progression free survival and overall survival being secondary outcomes. Univariable and multivariable logistic regression and Cox proportional hazard were performed, adjusting for known clinical predictors., Results: Metastatic melanoma specimens were available for 650 patients and primary specimens for 565 patients. No association was found in primary melanoma specimens. In metastatic specimens, a 10-point increase in the TILs-WG score was associated with a higher probability of response (aOR 1.17, 95 % CI 1.07-1.28), increased PFS (HR 0.93, 95 % CI 0.87-0.996), and OS (HR 0.94, 95 % CI 0.89-0.99). When categorized, patients in the highest tertile TILs-WG score (15-100 %) compared to the lowest tertile (0 %) had a longer median PFS (13.1 vs. 7.3 months, p = 0.04) and OS (49.4 vs. 19.5 months, p = 0.003). Similar results were noted using the MIA and Clark scores., Conclusion: In advanced melanoma patients, TIL patterns on H&E slides of pre-treatment metastases, regardless of measurement method, are independently associated with ICI response. TILs are easily scored on readily available H&Es, facilitating the use of this biomarker in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Karijn P.M. Suijkerbuijk reports financial support was provided by Netherlands Organisation for Health Research and Development. Karijn P.M. Suijkerbuijk reports financial support was provided by Hanarth Fund Foundation. Karijn P.M. Suijkerbuijk reports financial support was provided by Philips. Dr. de Groot reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Dr. De Groot has advisory board relationships with BMS. Dr. Aarts has advisory board / consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, Bayer and received research grants from Merck-Pfizer and all were paid to the institution and not related to current work. Dr. Hospers has consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi and Pierre Fabre and has received research grants from Bristol Myers Squibb and Seerave and all were paid to the institution. Dr. Kapiteijn has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly and Bayer not related to current work and paid to institute, and received research grants not related to this paper from Bristol Myers Squibb, Delcath and Pierre-Fabre. Dr. Piersma had advisory board relationships with BMS, Novartis and Pierre Fabre, honoraria were paid to institution. Dr. Suijkerbuijk has consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre Novartis, Sairopa, received honoraria from Novartis, Roche, Merck Sharp and Dome and received research funding from TigaTx, Bristol Myers Squibb and Philips and all were paid to institution and not related to the study. Dr. Schrader received honoraria/research funding from Kyowa Kirin paid to the institution and not related to the study. The remaining authors of this manuscript have no conflicts of interest to disclose. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mutant BRAF is a critical oncogenic driver in melanoma, making it an attractive therapeutic target. However, the success of targeted therapy using BRAF inhibitors vemurafenib and dabrafenib has been limited due to development of resistance, restricting their clinical efficacy. A prior knowledge of resistance mechanisms to BRAFi or any cancer drug can lead to development of drugs that overcome resistance thus improving clinical outcomes. In vitro cellular models are powerful systems that can be utilized to mimic and study resistance mechanisms. In this study, we employed a multi-omics approach to characterize a panel of BRAF mutant melanoma cell lines to develop and systematically characterize BRAFi persister and resistant cells using exome sequencing, proteomics and phosphoproteomics. Our datasets revealed frequently observed intrinsic and acquired, genetic and non-genetic mechanisms of BRAFi resistance that have been studied in patients who developed resistance. In addition, we identified proteins that can be potentially targeted to overcome BRAFi resistance. Overall, we demonstrate that in vitro systems can be utilized not only to predict resistance mechanisms but also to identify putative therapeutic targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patient demographics and shared decision making might influence the choice of adjuvant therapy for stage III melanoma., Objective: To identify factors for treatment selection of patients diagnosed with stage III melanoma to better understand current treatment decisions and improve further treatment counseling., Patients and Methods: Data from 2007 patients diagnosed with stage III melanoma, between December 2018 and 2021, sourced from the Dutch Cancer Registry, were analyzed., Results: Among the cohort, 48.7% received no therapy, 45.8% received checkpoint inhibition, and 5.5% received targeted therapy (TT). Patients foregoing therapy were significantly older [67.0 years (range 53.0-77.0) vs. 62.0 year (range 52.0-72.0)], had poorer performance scores (PS), and higher Charlson Comorbidity Index scores compared to those receiving therapy (p < 0.001). Patients undergoing therapy had significantly higher median Breslow thickness (3.3 mm vs. 2.2 mm) and higher prevalence of ulceration (49.9% vs. 38.1%). Those with connective tissue disease and/or congestive heart disease were more likely to receive TT [odds ration (OR) 8.1; 95% confidence interval (CI) 1.7-37.6 and OR 9.3; 95% CI 1.2-72.2, respectively]. Median treatment time among strata for disease recurrence was 4.26 months (3.69-4.82) for immunotherapy and 3.1 months (0.85-5.36) for TT (p = 0.298). Patients who developed recurrent disease were equal across treatment types (p = 0.656). The number of patients with grade 3 complications was different for each treatment type [immunotherapy: 17.8% vs. TT: 37.3% (p < 0.001)]., Conclusions: Age, PS, and Breslow thickness seem to influence adjuvant treatment decisions. Clinicians' preference for immunotherapy might play a role in counseling BRAF-positive patients for adjuvant therapy, this however, cannot be confirmed in this dataset. Overall, only a small proportion of patients completed adjuvant treatment., (© 2024. The Author(s).)

Melanoma is the most common skin cancer in children. While the current literature establishes treatment protocols for adult-type melanoma, very few pediatric-specific studies exist, and children are often excluded from melanoma clinical trials 2 . We report a case series of 23 pediatric patients aged 2-20 years old diagnosed with melanoma at the University of Rochester Medical Center between 1/1/2011 and 1/1/2022. 9/23 patients were Stage III; all patients underwent wide local excision and 9 received adjuvant therapies. 2/23 (8.7%) patients had recurrence of their malignancy after therapy while 21/23 (91.3%) remained without disease progression; 1 patient died from unknown cause, but the rest are alive and currently without disease. All patients whose initial therapy included nivolumab in addition to wide local excision did not have recurrence or progression of their disease. This case series highlights trends in the presentation, treatment, and outcomes of pediatric melanoma; however, additional multi-center studies are needed to establish the clinical utility of such features in pediatric melanoma.

Cyclopropenone is a valuable electrophilic reagent that can react with electrophilic reagents, nucleophilic reagents, free radicals, organic metals, etc. Furthermore, cyclopropenone derivatives have shown significant biological activity in various diseases, such as triple-negative breast cancer (TNBC), melanoma, and alopecia areata (AA). The cyclopropenone analogue diphenylcyclopropenone (DPCP) has been approved for the treatment of AA. Given the potential therapeutic benefits of cyclopropenone derivatives, this review aims to systematically summarize the structures, synthesis routes, and potential pharmacological functions of cyclopropenone analogues in the hope of offering novel insights for further rational design of more drugs based on the cyclopropenone skeleton for the treatment of human diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tartrolon D (TRL) is produced by Teredinibacter turnerae, a symbiotic cellulose-degrading bacteria in shipworm gills. Immunogenic cell death (ICD) induction contributes to a better and longer-lasting response to anticancer treatment. Tumor cells undergoing ICD trigger activation of the immune system, as a vaccine., Aims: This study aimed to evaluate ICD induction by TRL., Main Methods: Cell viability was evaluated by SRB assay. Cell stress, cell death, ICD features and antigen-presenting molecules were evaluated by flow cytometry and immunoblot., Key Findings: TRL showed antiproliferative activity on 7 tumor cell lines (L929, HCT 116, B16-F10, WM293A, SK-MEL-28, PC-3M, and MCF-7) and a non-tumor cell (HEK293A), with an inhibition concentration mean (IC 50 ) ranging from 0.03 μM to 13 μM. Metastatic melanomas, SK-MEL-28, B16-F10, and WM293A, were more sensitive cell lines, with IC 50 ranging from 0.07 to 1.2 μM. TRL induced apoptosis along with autophagy and endoplasmic reticulum stress and release of typical damage-associated molecular patterns (DAMPs) of ICD such calreticulin, ERp57, and HSP70 exposure, and HMGB1 release. Additionally, melanoma B16-F10 exposed to TRL increased expression of antigen-presenting molecules MHC II and CD1d and induced activation of splenocytes of C57BL/6 mice., Significance: In spite of recent advances provided by target therapy and immunotherapy, advanced metastatic melanoma is incurable for more than half of patients. ICD inducers yield better and long-lasting responses to anticancer treatment. Our findings shed light on an anticancer candidate of marine origin that induces ICD in melanoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Melanoma is the most aggressive form of skin cancer and originates from genetic mutations in melanocytes. The disease is multifactorial, but its main cause is overexposure to UV radiation. Currently, available chemotherapy expresses little to no results, which may justify the extensive use of natural products to treat this cancer. In this study, we reviewed the inhibition of melanoma angiogenesis by natural products and its potential mechanisms using literature from PubMed, EMBASE, Web of Science, Ovid, ScienceDirect and China National Knowledge Infrastructure databases. According to summarizes 27 natural products including alkaloids, polyphenols, terpenoids, flavonoids, and steroids that effectively inhibit angiogenesis in melanoma. In addition to these there are 15 crude extracts that can be used as promising agents to inhibit angiogenesis, but their core components still deserve further investigation. There are current studies on melanoma angiogenesis involving oxidative stress, immune-inflammatory response, cell proliferation and migration and capillary formation. The above natural products can be involved in melanoma angiogenesis through core targets such as VE-cadherin, COX-2, iNOS, VEGF, bFGF, FGF2,MMP2,MMP9,IL-1β,IL-6 play a role in inhibiting melanoma angiogenesis. Effective excavation of natural products can not only clarify the mechanism of drug action and key targets, but also help to promote the preclinical research of natural products for melanoma treatment and further promote the development of new clinical drugs, which will bring the gospel to the vast number of patients who are deeply afflicted by melanoma., Competing Interests: Declaration of competing interest All authors agreed with the submission, and the authors declared no competing financial interest in this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Croton genus (Euphorbiaceae) is recognized as a promising source for identifying bioactive compounds with antiproliferative activity. However, knowledge on the chemical composition and activity of Croton floribundus, Croton echinocarpus, and Croton zehntneri is limited. Thus, this study aimed to investigate the antiproliferative activity of these species on cells derived from tumoral breast, lung, and melanoma cells, and primary fibroblasts derived from human skin. Metabolomic strategies were applied via ultra-performance liquid chromatography coupled with high-resolution mass spectrometry and multivariate statistical analysis to target the main active compound. The C. floribundus leaf extract exhibited the highest activity, with an IC 50 value lower than that of the reference drug - temozolomide - in the most responsive cell line - SK-MEL-147 - and in all the evaluated melanoma cell lines (SK-MEL-147, CHL-1 and WM-1366). Four tetrahydrofurofuran lignans were isolated for the first time from the most promising fraction of the C. floribundus extract. According to the metabolomic and multivariate statistical analyses, the isolated lignan epi-yangambin constituted the main antiproliferative compound against SK-MEL-147; furthermore, it exhibited selective antiproliferative activity for this cell line (IC 50  = 13.09 μg/mL and selectivity index = 3.82; temozolomide, IC 50  = 121.50 μg/mL) due to, at least in part, its ability to inhibit cell cycle progression at G2/M. This is especially relevant considering the high resistance of melanoma cells to available drugs. Thus, epi-yangambin can serve as a prototype for further antiproliferative investigations., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Most clinical trials investigating targeted therapies for patients harboring BRAF V600 mutations have included mostly White patients, and data for Asian patients are scarce. Although there are several retrospective studies in Japanese patients, they have investigated only the dabrafenib + trametinib regimen, and have had a short follow-up period. We conducted a single-center retrospective study to update previous studies and compare the outcomes with those in White patients. We analyzed 89 patients who received dabrafenib + trametinib or encorafenib + binimetinib, including 11 who received both treatment regimens. The overall response rate was 79.8%, with complete response in 25 patients (28.1%) and partial response in 45 patients (51.7%). The median progression-free survival was 13.7 months, and the median overall survival was 32.9 months. The 3-year progression-free and overall survival rates were 31.8% and 47.9%, respectively. Although the two regimens showed no significant differences in efficacy, their safety profiles differed, as reported in clinical trials. Therefore, the most frequent adverse event associated with the dabrafenib + trametinib regimen was pyrexia (61.3%) and that of encorafenib + binimetinib was blurred vision (32.0%). Switching directly to another targeted therapy after progressive disease showed no clinical response; however, rechallenge followed by immune checkpoint inhibitor therapy showed a certain response. As a prognostic factor, performance status was associated with progression-free survival, and performance status, serum lactate dehydrogenase level, and dose interruption were associated with overall survival in the multivariate analysis. Real-world data on targeted therapy for patients with melanoma in Japan suggest that both dabrafenib + trametinib and encorafenib + binimetinib show similar efficacy and safety in Asian and White patients., (© 2024 Japanese Dermatological Association.)

Melanoma is the third most common malignant skin tumor and has increased in morbidity and mortality over the previous decade due to its rapid spread into the bloodstream or lymphatic system. This study used integrated bioinformatics and network-based methodologies to reliably identify molecular targets and small molecular medicines that may be more successful for Melanoma diagnosis, prognosis and treatment. The statistical LIMMA approach utilized for bioinformatics analysis in this study found 246 common differentially expressed genes (cDEGs) between case and control samples from two microarray gene-expression datasets (GSE130244 and GSE15605). Protein-protein interaction network study revealed 15 cDEGs (PTK2, STAT1, PNO1, CXCR4, WASL, FN1, RUNX2, SOCS3, ITGA4, GNG2, CDK6, BRAF, AGO2, GTF2H1 and AR) to be critical in the development of melanoma (KGs). According to regulatory network analysis, the most important transcriptional and post-transcriptional regulators of DEGs and hub-DEGs are ten transcription factors and three miRNAs. We discovered the pathogenetic mechanisms of MC by studying DEGs' biological processes, molecular function, cellular components and KEGG pathways. We used molecular docking and dynamics modeling to select the four most expressed genes responsible for melanoma malignancy to identify therapeutic candidates. Then, utilizing the Connectivity Map (CMap) database, we analyzed the top 4-hub-DEGs-guided repurposable drugs. We validated four melanoma cancer drugs (Fisetin, Epicatechin Gallate, 1237586-97-8 and PF 431396) using molecular dynamics simulation with their target proteins. As a result, the results of this study may provide resources to researchers and medical professionals for the wet-lab validation of MC diagnosis, prognosis and treatments.Communicated by Ramaswamy H. Sarma.

Competing Interests: BO'C has received travel support from Bristol Myers Squibb. PC has received institutional research funding, advisory board, speaker fees, and travel support from Merck Sharpe & Dohme; institutional research funding and speaker fees from Pierre Fabre; advisory board fees from Bristol Myers Squibb; and has participated on data and safety monitoring boards for IO Biotech and Amgen.

Combination therapy using chemo-photothermal therapy (chemo-PTT) shows great efficacy toward tumor ablation in preclinical studies. Besides, lipopolymersomes as a hybrid nanocarriers, integrate advantages of liposomes and polymersomes in a single platform in order to provide tremendous biocompatibility, biodegradability, noteworthy loading efficacy for both hydrophobic and hydrophilic drugs with adjustable drug release and high stability. In this study, a multipurpose lipopolymersome was fabricated for guided chemotherapy-PTT and NIR-imaging of melanoma. A lipopolymerosomal hybrid nanovesicle consisting of equal molar ratio of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) diblock copolymer (molar ratio 1:1) was fabricated. The nanoparticulate system was prepared through film rehydration technique for encapsulation of doxorubicin (DOX) and indocyanine green (ICG) to form DOX-ICG-LP platform. At the next stage, AS1411 DNA aptamer was conjugated to the surface of lipopolymersome (Apt-DOX-ICG-LP) for selective delivery. The sizes of DOX-ICG-LP and Apt-DOX-ICG-LP were obtained through DLS analysis (61.0 ± 6 and 74 ± 5, respectively). Near Infrared-responsive release pattern of the prepared lipopolymersome was verified in vitro. The formulated platform showed efficient photothermal conversion, and superior stability with acceptable encapsulation efficiency. Consistent with the in vitro studies, NIR-responsive lipopolymersome exhibited significantly higher cellular toxicity for Chemo-PTT versus single anti-cancer treatment. Moreover, superlative tumor shrinkage with favorable survival profile were attained in B16F10 tumor-bearing mice received Apt-DOX-ICG-LP and irradiated with 808 nm laser compared to those treated with either DOX-ICG-LP or Apt-DOX-ICG-LP without laser irradiation. The diagnostic capability of Apt-DOX-ICG-LP was addressed using in vivo NIR imaging, 6 and 24 h post-intravenous administration. The results indicated desirable feature of an established targeted theranostic capability of Apt-DOX-ICG-LP for both diagnostics and dual chemo-PTT of melanoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Immunotherapy has transformed the treatment of advanced melanoma. However, up to two-thirds of patients experience disease progression after initially achieving a response to immunotherapy. Furthermore, most research has focused on cutaneous melanoma rather than acral or mucosal melanoma, although the latter predominates in Asian populations. In this review, we examine and summarize current definitions of resistance to immunotherapy and the epidemiology of resistance to PD-1 inhibition. We also review the available literature on molecular mechanisms of resistance, including how the tumor mutational landscape and tumor microenvironments of immunotherapy-resistant acral and mucosal melanomas may influence resistance. Finally, we review strategies for overcoming resistance to PD-1 inhibition and summarize completed studies and ongoing clinical trials. Our review highlights that improving the understanding of resistance mechanisms, optimizing existing therapies and further studying high-risk populations would maximize the potential of immunotherapy and result in optimized treatment outcomes for patients with melanoma., Competing Interests: Declaration of Competing Interest Hongwei Fan and Li Zhang are employees of MSD China. The other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Our goal was to compare molecular and immune profiles of vulvovaginal melanoma (VVM) with cutaneous melanoma (CM) and explore the significance of immune checkpoint inhibitor (ICI) agents on survival., Methods: Samples from VVM and CM tumors underwent comprehensive molecular and immune profiling. Treatment and survival data were extracted from insurance claims data and OS was calculated from time of ICI treatment to last contact. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons., Results: Molecular analysis was performed on 142 VVM and 3823 CM tumors. VVM demonstrated significantly (q < 0·01) less frequent BRAF and more frequent KIT, ATRX, and SF3B1 mutations. Alterations in pathways involving DNA damage and mRNA splicing were more common in VVM, while alterations in cell cycle and chromatin remodeling were less common. Immunogenicity of VVM was lower than CM, with an absence of high TMB (0% vs 46.9%) and lower PD-L1 positivity (18·0% vs 29·5%). Median immune checkpoint gene expression was lower in VVM, as were cell fractions for type I macrophages and CD8+ T-cells(q < 0·01). Myeloid dendritic cells were increased in VVM(q < 0·01). Median OS was shorter for VVM than for CM patients treated with ICIs (17·6 versus 37·9 months, HR:1·65 (95% CI 1·02-2·67) p = 0·04)., Conclusions: VVM has a distinct molecular and immune profile compared to CM, which may contribute to the worse survival in VVM compared to CM patients treated with ICI therapy. Though ICIs have been a mainstay of treatment in recent years, our findings suggest that new therapeutic strategies are needed., Competing Interests: Declaration of competing interest SW and JX are employees of Caris Life Sciences. GTG reports grants from Exelixis and Luceno Dynamics; fees for consulting for Bristol Myers Squibb, Merck, Novartis, Regeneron, Immunocore, Iovance, Lyell Immunopharma, Eisai, Incyte, Pfizer, Sapience Therapeutics, Exicure, and Genentech; fees for payment/honoraria from Immunocore; fees for participation on a Data Safety Monitoring Board/Advisory Board for Huyabio. GKI reports fees for consulting for Sanofi and Pfizer; fees for payment/honoraria from Merck, Sanofi, and Regeneron; fees for support for attending meetings from BMS and Sanofi; fees for participation on a Data Safety Monitoring Board/Advisory Board from Replimune, Castle, and Regeneron; institutional research support from BMS, Regeneron, Replimune, Pfizer, InstilBio, Checkmate Pharmaceuticals, and Xencor. TJH reports consulting fees from J & J, Clovis, AstraZeneca, GSK, Roche Genentech, Caris, Genelux, Aravive, Merck, Eisai, and Seagen. BKE reports fees for participation on a Data Safety Monitoring Board/Advisory Board for Merck and GSK. JB reports fees for consulting for Caris, AstraZeneca, Genentech, GSK Tesaro, and Verastem; fees for participation on a Data Safety Monitoring Board/Advisory Board from Caris, AstraZeneca, GSK Tesaro, and Verastem; fees for a leadership/fiduciary role from American Association of Gynecologic Laparoscopy, and Society of Gynecologic Oncology. The remaining authors have nothing to disclose. All of these disclosures mentioned above are unrelated to this study. No author declares a conflict of interest related to the study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibition has transformed the treatment landscape of advanced melanoma and long-term survival of patients is now possible. However, at least half of the patients do not benefit sufficiently. Metabolic reprogramming is a hallmark of cancer cells and may contribute to both tumour growth and immune evasion by the tumour. Preclinical studies have indeed demonstrated that modulating tumour metabolism can reduce tumour growth while improving the functionality of immune cells. Since metabolic pathways are commonly shared between immune and tumour cells, it is essential to understand how modulating tumour metabolism in patients influences the intricate balance of pro-and anti-tumour immune effects in the tumour microenvironment. The key question is whether modulating tumour metabolism can inhibit tumour cell growth as well as facilitate an anti-tumour immune response. Here, we review current knowledge on the effect of tumour metabolism on the immune response in melanoma. We summarise metabolic pathways in melanoma and non-cancerous cells in the tumour microenvironment and discuss models and techniques available to study the metabolic-immune interaction. Finally, we discuss clinical use of these techniques to improve our understanding of how metabolic interventions can tip the balance towards a favourable, immune permissive microenvironment in melanoma patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Melanoma metabolism can be reprogrammed by activating BRAF mutations. These mutations are present in up to 50% of cutaneous melanomas, with the most common being V600E. BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation. Prior to the development of targeted anti-BRAF therapies, these mutations were associated with accelerated clinical disease in the metastatic setting. Combination BRAF and MEK inhibition is a first line treatment option for locally advanced or metastatic melanoma harboring targetable BRAF mutations. This therapy shows excellent response rates but these responses are not durable, with almost all patients developing resistance. When BRAF mutated melanoma cells are inhibited with targeted therapies the metabolism of those cells also changes. These cells rely less on glycolysis for energy production, and instead shift to a mitochondrial phenotype with upregulated TCA cycle activity and oxidative phosphorylation. An increased dependence on glutamine utilization is exhibited to support TCA cycle substrates in this metabolic rewiring of BRAF mutated melanoma. Herein we describe the relevant core metabolic pathways modulated by BRAF inhibition. These adaptive pathways represent vulnerabilities that could be targeted to overcome resistance to BRAF inhibitors. This review evaluates current and future therapeutic strategies that target metabolic reprogramming in melanoma cells, particularly in response to BRAF inhibition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: In the European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 study, adjuvant pembrolizumab improved recurrence-free survival and distant-metastasis-free survival in patients with resected stage III melanoma. Earlier results showed no effect of pembrolizumab on health-related quality of life (HRQOL). Little is known about HRQOL after completion of treatment with pembrolizumab, an important research area concerning patients who are likely to become long-term survivors. This study reports long-term HRQOL results., Methods: This double-blind, randomised, controlled, phase 3 trial compared adjuvant pembrolizumab with placebo in patients aged 18 years or older with previously untreated stage IIIA, IIIB, or IIIC resected cutaneous melanoma and an Eastern Cooperative Oncology Group performance status score of 1 or 0, recruited from 123 academic centres and community hospitals in 23 countries. Patients were randomly assigned (1:1) with a minimisation technique stratified for stage and geographical region to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for up to 18 doses. Investigators, patients, and those collecting or analysing data were masked to group assignment. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, measured with the EORTC Quality of Life Questionnaire-Core 30. All patients with a baseline HRQOL evaluation available who were alive 108 weeks from randomisation were included in this analysis of long-term HRQOL. Long-term HRQOL included assessments measured every 6 months between 108 weeks and 48 months after randomisation. The threshold of clinical relevance for all HRQOL scales used was an average change of 5 points. The trial is ongoing, recruitment is completed, and HRQOL data collection is finalised. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were randomly assigned to pembrolizumab (n=514) or placebo (n=505). Completion of the HRQOL evaluation at baseline exceeded 90% (481 [94%] patients in the pembrolizumab group and 467 [92%] in the placebo group), and ranged between 60% and 90% for post-baseline timepoints. Among patients with a baseline HRQOL evaluation, 365 (39%) were female and 583 (61%) were male. The mean change from baseline to long-term HRQOL was -0·56 (95% CI -2·33 to 1·22) in the pembrolizumab group and 1·63 (-0·12 to 3·38) in the placebo group. The difference between the two groups was -2·19 (-4·65 to 0·27, p=0·081). Differences for all other scales were smaller than 5 and not statistically significant., Interpretation: Adjuvant pembrolizumab did not have a significant impact on long-term HRQOL compared with placebo in patients with resected stage III melanoma. These findings, together with earlier results on efficacy and HRQOL, support the use of pembrolizumab in this setting., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests EB's spouse and daughter hold shares in Sandoz, Galenica, Alcon, Roche, and Novartis. MK reports study funding paid to the institution by Merck Sharp & Dohme (MSD) since the initial planning of the work, and study funding paid to the institution from Bristol Myers Squibb (BMS), Immunocore, Johnson & Johnson, and Pierre Fabre in the past 36 months. MM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sun Pharma. GVL reports consulting fees from Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics, IOBiotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR, Pierre Fabre, Regeneron, Scancell, and SkylineDX BV. VA reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD, Novartis; support from BMS for attending meetings or travel; participation on a data safety monitoring board or advisory board for BMS, MSD, Novartis, and Immunocore; CUB reports personal fees from MSD, grants and personal fees from Novartis and BMS, personal fees from Roche, GSK, AstraZeneca, Pfizer, Lilly, GenMAB, Pierre Fabre, and Third Rock ventures, grants from NanoString and 4SC, during the conduct of the study. CUB has patents pending (WO 2021/177822 A1 and WO 2023/022596 A1), and reports stock ownership: co-founder of Immagene BV and Signature Oncology. AH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, and Novartis; payments for participation on a data safety monitoring board or advisory board with BMS, MSD, and Novartis. SD reports research funding from BMS, MSD, and Pierre Fabre to the institution; payment or honoraria to the institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS and MSD; support for attending meetings or travel from BMS and MSD; trim 24 patent pending; participation on a data safety monitoring board or advisory board at BMS and MSD, with payments made to the institution; spouse being a Sanofi employee. AK reports consulting fees for an advisory role at Moderna and speaker honorarium from MSD. MSC reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD and Novartis; having served on advisory boards for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi. AM reports support of scientific and educational conference from Janssen. SS reports grants or contracts from Novartis/Advanced Accelerator Applications (AAA), AstraZeneca, MSD, Genentech, Senhwa, and Pfizer; funding goes to the institution to undertake investigator initiated clinical trial and translational research. SS reports participation on advisory boards for MSD, BMS, AstraZeneca—fees for attending go to research funds at the institution. SS is the chair of DSMB for two Novartis/AAA sponsored phase 3 trials—no fee accepted for chair role. SP reports payment or honoraria to her and her institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, and Novartis, and to her partner and her institution from Amgen and Phylogen; payments to her institution for participation on a data safety monitoring board or advisory board with MSD; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid from GEM, EORTC melanoma group, and ASEICA. DS reports research grants to his institution from Amgen, Array/Pfizer, BMS, MSD, Novartis, and Roche; consulting fees paid personally from 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Innovent, Labcorp, Merck Serono, MSD, Nektar, Neracare, Novartis OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Merck Serono, Novartis, Roche, Sanofi, and SunPharma; personal support for attending meetings or travel from BMS, Merck Serono, MSD, Novartis, Sanofi, and Pierre Fabre; personal payments for participation on a data safety monitoring board or advisory board at 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Merck Serono, MSD, Nektar, Neracare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; leadership or fiduciary role, paid or unpaid, at Dermatologic Cooperative Oncology Group, German Cancer Society, Hiege Stiftung, Deutsche Hautkrebsstiftung, Nationale Versorgungskonferenz Hautkrebs eV, and European Melanoma Registry; drug supply (nivolumab, ipilimumab) from BMS. RJ reports research funding from Iovance Biotherapeutics; honoraria for advisory role or speaker presentation from Merck, BMS, Medison, Pfizer, and Novartis. PR reports consulting fees paid to himself from MBS, MSD, Novartis, Pierre Fabre, Philogen, and Pfizer; honoraria for lectures, presentations, speakers bureau, manuscript writing, or educational events paid to himself from BMS, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, MSD, and AstraZeneca; speakers bureau Pfizer, Novartis, Pierre Fabre, MSD, and BMS paid to himself; support for attending meetings or travel from Orphan Europe and Pierre Fabre paid to himself; research funding to his institution from Novarits, Pfizer, Roche, and BMS. AJMvdE reports study grants from BMS and Idera; travel expenses from Ipsen; advisory board from BMS, MSD Oncology, Ipsen, Pierre Fabre, and Janssen Cilag BV. CC reports support for attending meetings or travel from Orphan Europe and Pierre Fabre. DG reports stock or stock options from Merck & Co. CK reports stock or stock options from Merck & Co and being an employee of Merck & Co. CR reports consulting fees (payments made to her) from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma, and IO Biontech; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (payments made to her) from Pierre Fabre, Sanofi, BMS, MSD, and Novartis; support for attending meetings or travel from Pierre Fabre; participation on a data safety monitoring board or advisory board (payments made to her) with BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, Egle, Philogen, and Maat Pharma. AMME reports honoraria for scientific advisory board or independent data monitoring committee functions from Agenus, BioInvent, BioNTech, Boehringer Ingelheim, Brenus, CatalYm, Ellipses, EikonTX, Eurobio, Galecto, IO Biotech, IQVIQ, ISA Pharmaceuticals, Merck & Co, MSD, Pfizer, Pierre Fabre, Scorpion TX, Sairopa, Sellas, SkylineDX, TigaTx, and Trained Therapeutics Discovery; honoraria from Acetra, GenOway, GSK, Moderna, and Trained Immunity Tx; equity from IO Biotech, Sairopa, and SkylineDx; being the Editor in Chief of the European Journal of Cancer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date., Methods: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV., Results: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2)., Conclusions: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations., Competing Interests: Declaration of Competing Interest All other authors declare no conflicts of interest for the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Therapy with immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of metastatic melanoma but is also associated with various immune-related adverse events (AE), including pulmonary toxicity. Herein, we describe the case of a 60-year-old female with metastasized melanoma with BRAF mutation under combination immunotherapy with ipilimumab and nivolumab, who presented with a persistent, nonproductive cough for the last two months. Her CT-scan showed de novo bronchial inflammation and wall thickening in all lung fields. Initial treatment with antimicrobial treatment and inhalation corticosteroids did not resolve her symptoms, nor the radiologic abnormalities. Additional testing with transbronchial cryobiopsy showed a histologic picture of diffuse ill-formed granulomas and the presence of moderate chronic active inflammation of the respiratory epithelium, consistent with medication-related bronchiolitis. Bronchiolitis, as present in this case, has rarely been reported as an immune-related AE. A thorough diagnostic workup is mandatory as it remains a diagnosis of exclusion. Management consists of discontinuing ICIs and administering systemic corticosteroids. The addition of immunosuppressive agents (e, infliximab, cyclophosphamide, or mycophenolate mofetil) can be considered in refractory cases. In our case, clinical and radiologic resolution was achieved after discontinuing the ICI and treatment with high-dose prednisone. This case shows that although bronchiolitis is a rare immune-related side effect of ICIs, oncologists, and pulmonologists should always be aware of this relatively easily treatable AE., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Uveal melanoma (UM) is genetically a distinct tumor compared to cutaneous melanoma (CM), and due to its low mutational burden, it is far less perceptible to the immune system. Thus, treatments that have revolutionized the treatment of CM remain widely inefficient in metastatic UM or only demonstrate effectiveness in a small subpopulation of patients. To this end, the therapeutic benefit of immune checkpoint blockade is very limited and may come at the expense of severe immune-related adverse events that could potentially affect all organ systems. Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. It is the first agent that demonstrated a survival advantage in a randomized controlled trial of metastatic UM patients. Despite the survival benefit and approval, the restriction of tebentafusp to HLA-A*02:01-positive patients and the low objective response rate indicate the persistent need for additional therapies. Thus, liver-directed therapies are commonly used for tumor control of hepatic metastases and represent a central pillar of the daily management of liver-dominant disease. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM., (© 2024. The Author(s).)

The use of disease-modifying therapies (DMT) has led to a paradigm shift in the management of multiple sclerosis. A comprehensive narrative review was conducted through an extensive literature search including Medline and Google Scholar to elucidate the link between DMT and the propensity of cutaneous malignancies. Sphingosine-1-phosphate receptor modulators, such as fingolimod and siponimod are associated with a higher risk of basal cell carcinoma (BCC), but not squamous cell carcinoma, or melanoma. The associated physiopathological mechanisms are not fully understood. Alemtuzumab and cladribine show isolated associations with skin cancer. Regarding other DMT, no increased risk has ever been found. Given the evidence currently available, it is of paramount importance to advocate for necessary dermatological assessments that should be individualized to the risk profile of each patient. Nonetheless, additional prospective studies are still needed to establish efficient dermatological follow-up protocols., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Central nervous system (CNS) metastases from lung cancers and melanoma, significantly contribute to morbidity and mortality. Despite advances in local therapies, there is a need for effective systemic treatments. Pembrolizumab, a PD-1 inhibitor, has shown promise for some patients with untreated brain metastases from melanoma and non-small cell lung cancer (NSCLC). This study aims to analyze the response of brain metastasis to pembrolizumab and associate characteristics like size and location with treatment outcome., Methods: This retrospective study used imaging data from a phase II trial of pembrolizumab in melanoma or NSCLC patients with untreated brain metastases. MRI evaluations were conducted at 2 month intervals, with each brain metastasis treated as a distinct tumor for response assessment, based on modified RECIST criteria (maximum 5 lesions, 5 mm target lesions)., Results: Of 130 individual target metastases (> 5 mm), in 65 patients with NSCLC (90 metastases) and Melanoma (40 metastases), 32 (24.6%) demonstrated complete resolution, 24 (18.5%) had partial resolution, 32 (24.6%) were SD and 42 (32.3%) demonstrated PD. Those smaller than 10 mm were more likely to show complete resolution (p = 0.0218), while those ≥ 10 mm were more likely to have PR. There was no significant association between size, number or location (supratentorial vs. infratentorial) and lesion progression. The median time to metastatic lesion progression in the brain was 5.7-7 weeks., Conclusion: Pembrolizumab is effective in brain metastases from NSCLC and melanoma, showing response (CR + PR) in 43% and progression (PD) in 32% of metastases. With the median time to CNS progression of 5.7-7 weeks, careful radiographic monitoring is essential to guide timely local treatment decisions., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acquired drug resistance is the major cause for disease recurrence in cancer patients, and this is particularly true for patients with metastatic melanoma that carry a BRAF V600E mutation. To address this problem, we investigated cyclic membrane-active peptides as an alternative therapeutic modality to kill drug-tolerant and resistant melanoma cells to avoid acquired drug resistance. We selected two stable cyclic peptides (cTI and cGm), previously shown to have anti-melanoma properties, and compared them with dabrafenib, a drug used to treat cancer patients with the BRAF V600E mutation. The peptides act via a fast membrane-permeabilizing mechanism and kill metastatic melanoma cells that are sensitive, tolerant, or resistant to dabrafenib. Melanoma cells do not become resistant to long-term treatment with cTI, nor do they evolve their lipid membrane composition, as measured by lipidomic and proteomic studies. In vivo studies in mice demonstrated that the combination treatment of cTI and dabrafenib resulted in fewer metastases and improved overall survival. Such cyclic membrane-active peptides are thus well suited as templates to design new anticancer therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Stimulation of the innate immune stimulator of interferon genes (STING) pathway has been shown to boost anti-tumour immunity. Nevertheless, the systemic delivery of STING agonists to the tumour presents challenges. Therefore, we designed a cyclic dinucleotide (CDN)-based drug delivery system (DDS) combined photothermal therapy (PTT)/photodynamic therapy (PDT)/immunotherapy for cutaneous melanoma. We coencapsulated a reactive oxygen species (ROS)-responsive prodrug thioketone-linked CDN (TK-CDN), and photoresponsive agents chlorin E6 (Y6) within mitochondria-targeting reagent triphenylphosphonium (TPP)-modified liposomes (Lipo/TK-CDN/TPP/Y6). Lipo/TK-CDN/TPP/Y6 exhibited a photothermal effect similar to Y6, along with a superior cellular uptake rate. Upon endocytosis by B16F10 cells, Lipo/TK-CDN/TPP/Y6 generated large amounts of ROS under laser irradiation for PDT. Mice bearing B16F10 tumours were intravenously injected with Lipo/TK-CDN/TPP/Y6 and exposed to irradiation, resulting in a substantial inhibition of tumour growth. Exploration of the mechanism of anti-tumour action showed that Lipo/TK-CDN/TPP/Y6 had a stronger stimulation of STING activation and anti-tumour immune cell infiltration compared to other groups. Hence, the Lipo/TK-CDN/TPP/Y6 nanoparticles offer great potential as a DDS for targeted and on-demand drug release at tumour sites. These nanoparticles exhibit promise as a candidate for precise and controllable combination therapy in the treatment of tumours.

Uveal melanoma (UM) is a rare yet lethal primary intraocular malignancy affecting adults. Analysis of data from The Cancer Genome Atlas (TCGA) database revealed that FGFR1 expression was increased in UM tumor tissues and was linked to aggressive behavior and a poor prognosis. This study assessed the anti-tumor effects of Erdafitinib, a selective pan-FGFR inhibitor, in both in vitro and in vivo UM models. Erdafitinib exhibited a robust anti-cancer activity in UM through inducing ferroptosis in the FGFR1-dependent manner. Transcriptomic data revealed that Erdafitinib mediated its anti-cancer effects via modulating the ferritinophagy/lysosome biogenesis. Subsequent research revealed that Erdafitinib exerted its effects by reducing the expression of FGFR1 and inhibiting the activity of mTORC1 in UM cells. Concurrently, it enhanced the dephosphorylation, nuclear translocation, and transcriptional activity of TFEB. The aggregation of TFEB in nucleus triggered FTH1-dependent ferritinophagy, leading to lysosomal activation and iron overload. Conversely, the overexpression of FGFR1 served to mitigate the effects of Erdafitinib on ferritinophagy, lysosome biogenesis, and the activation of the mTORC1/TFEB signaling pathway. In vivo experiments have convincingly shown that Erdafitinib markedly curtails tumor growth in an UM xenograft mouse model, an effect that is closely correlated with a decrease in FGFR1 expression levels. The present study is the first to demonstrate that Erdafitinib powerfully induces ferroptosis in UM by orchestrating the ferritinophagy and lysosome biogenesis via modulating the FGFR1/mTORC1/TFEB signaling. Consequently, Erdafitinib emerges as a strong candidate for clinical trial investigation, and FGFR1 emerges as a novel and promising therapeutic target in the treatment of UM., (Copyright © 2024 Elsevier Inc. All rights reserved.)

L-asparaginase (L-ASNase) is an enzyme that catalyzes the hydrolysis of L-asparagine to L-aspartic acid and ammonia and is used to treat acute lymphoblastic leukemia. It is also toxic to the cells of some solid tumors, including melanoma cells. Immobilization of this enzyme can improve its activity against melanoma tumor cells. In this work, the properties of bacterial cellulose (BC) and feasibility of BC films as a new carrier for immobilized L-ASNase were investigated. Different values of growth time were used to obtain BC films with different thicknesses and porosities, which determine the water content and the ability to adsorb and release L-ASNase. Fourier transform infrared spectroscopy confirmed the adsorption of the enzyme on the BC films. The total activity of adsorbed L-ASNase and its release were investigated for films grown for 48, 72 or 96 h. BC films grown for 96 h showed the most pronounced release as described by zero-order and Korsmayer-Peppas models. The release was characterized by controlled diffusion where the drug was released at a constant rate. BC films with immobilized L-ASNase could induce cytotoxicity in A875 human melanoma cells. With further development, immobilization of L-ASNase on BC may become a potent strategy for anticancer drug delivery to superficial tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Melanoma is the most aggressive and deadly form of skin cancer, and its incidence has been steadily increasing over the past few decades, particularly in the Caucasian population. Immune checkpoint inhibitors (ICI), anti-PD-1 monotherapy or in combination with anti-CTLA-4, and more recently, anti-PD-1 plus anti-LAG-3 have changed the clinical evolution of this disease. However, a significant percentage of patients do not benefit from these therapies. Therefore, to improve patient selection, it is imperative to look for novel biomarkers. Immune subsets, particularly the quantification of lymphocyte T populations, could contribute to the identification of ICI responders. The main purpose of this review is to thoroughly examine significant published data on the potential role of lymphocyte T subset distribution in peripheral blood (PB) or intratumorally as prognostic and predictive of response biomarkers in advanced melanoma patients treated with ICI regardless of BRAFV600 mutational status.

Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with cancer. However, these therapies are associated with adverse events including de novo immune-related adverse events or flare of pre-exiting autoimmune disorders. Up to 80% of patients with cancer and pre-existing psoriasis (PsO) or psoriatic arthritis (PsA) experience PsO/PsA flare after initiating ICIs. Targeting the interleukin (IL)-17/IL-23 axis is a mainstream of the PsO/PsA treatment. However, whether this treatment can effectively control PsO/PsA with ICI exposure while preserving anti-tumour efficacy remains unknown., Case Reports: We report three patients with PsA and cancer, who received ICIs for their cancer treatment. All patients were male. Two patients had clear cell renal cell carcinoma, and one had melanoma. Two patients received anti-PD-1 antibody monotherapy, while one patient received combined anti-CTLA-4 and PD-1 antibody therapy. One patient had been receiving anti-IL-17A antibody (secukinumab), while the other two patients started anti-IL-17A antibody (ixekizumab) and anti-IL-23 antibody (guselkumab) after their PsA flared up during ICI treatment. Of note, with the anti-IL-17A or anti-IL-23 antibody treatment, their PsA remained in remission, and they well tolerated the ICI therapy. Importantly, all three patients showed persistent tumour responses to ICI therapy, including two complete remissions and one stable disease, respectively., Conclusions: These three cases suggest that targeting the IL-17/23 axis may be an effective and safe approach for patients with cancer and pre-existing PsA being considered for ICI therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Melanoma, arising from the malignant transformation of melanocytes, stands as the most lethal type of skin cancer. While significant strides have been made in targeted therapy and immunotherapy, substantially enhancing therapeutic efficacy, the prognosis for melanoma patients remains unoptimistic. SIRT7, a nuclear-localized deacetylase, plays a pivotal role in maintaining cellular homeostasis and adapting to external stressors in melanoma, with its activity closely tied to intracellular nicotinamide adenine dinucleotide (NAD + ). However, its involvement in adaptive resistance to targeted therapy remains unclear. Herein, we unveil that up-regulated SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Initially, we observed a significant increase of SIRT7 expression in publicly available datasets following targeted therapy within a short duration. In consistent, we found elevated SIRT7 expression in melanoma cells subjected to BRAF or MEK inhibitors in vitro. The up-regulation of SIRT7 expression was also confirmed in xenograft tumors in mice after targeted therapy in vivo. Furthermore, we proved that SIRT7 deficiency led to decreased cell viability upon prolonged exposure to BRAF or MEK inhibitors, accompanied by an increase in cell apoptosis. Mechanistically, SIRT7 deficiency restrained the upregulation of genes associated with mitochondrial biogenesis and intracellular ATP levels in response to targeted therapy treatment in melanoma cells. Ultimately, we proved that SIRT7 deficieny could sensitize BRAF-mutant melanoma cells to MAPK inhibition targeted therapy in vivo. In conclusion, our findings underscore the role of SIRT7 in fostering adaptive resistance to targeted therapy through the facilitation of mitochondrial biogenesis. Targeting SIRT7 emerges as a promising strategy to overcome MAPK inhibitor adaptive resistance in melanoma., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite unquestionable advances in therapy, melanoma is still characterized by a high mortality rate. For years, high expectations have been raised by compounds of natural origin as a component of pharmacotherapy, particularly by triterpenes found in the bark of birch trees. In this study, 3,4- seco -dammara-4(29),20(21),24(25)-trien-3-oic acid (SDT) was isolated from buds of silver birch and its mechanisms of cell death induction, including apoptosis and autophagy, were determined. Cytotoxicity of SDT was evaluated by the cell viability test and clonogenic assay, whereas induction of apoptosis and autophagy was determined by annexin V staining and Western blot. The results revealed dose- and time-dependent reductions in viability of melanoma cells. Treatment of cells for 48 h led to an increase in the percentage of annexin V-positive cells, activation of caspase-8, caspase-9, and caspase-3, and cleavage of PARP, confirming apoptosis. Simultaneously, it was found that SDT increased the level of autophagy marker LC3-II and initiator of autophagy beclin-1. Pretreatment of cells with caspase-3 inhibitor or autophagy inhibitor significantly reduced the cytotoxicity of SDT and revealed that both apoptosis and autophagy contribute to a decrease in cell viability. These findings suggest that 3,4- seco -dammaranes may become a promising group of natural compounds for searching for anti-melanoma agents.

Objective: This study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC)., Design, Setting and Participants: This is a phase 1-1b/2, open-label, multinational, multicentre study of patients with advanced/metastatic melanoma or NSCLC with ≥1 measurable lesion., Interventions: Patients were given sabatolimab 800 mg every 4 weeks plus spartalizumab 400 mg every 4 weeks until unacceptable toxicity, disease progression and/or treatment discontinuation., Outcome Measures: The phase 2 primary outcome measure was overall response rate and secondary objectives included evaluation of the safety, tolerability, efficacy and pharmacokinetics of sabatolimab in combination with spartalizumab., Results: 33 patients (melanoma n=16, NSCLC n=17) received sabatolimab plus spartalizumab. 31 (94%) experienced ≥1 adverse event (AE); 15 (46%) experienced grade 3/4 events. The most frequent grade ≥3 AEs for NSCLC were anaemia, dyspnoea and pneumonia (each n=2, 12%); for patients with melanoma, the most frequent grade ≥3 AEs were physical health deterioration, hypokalaemia, hypophosphataemia, pathological fracture and tumour invasion (each n=1; 6%). One (3%) patient discontinued treatment due to AE. Stable disease was seen in three patients with melanoma (19%) and six patients with NSCLC (35%). Median progression-free survival was 1.8 (90% CI 1.7 to 1.9) and 1.7 (90% CI 1.1 to 3.4) months for patients with melanoma and NSCLC, respectively. Patients with stable disease had higher expression levels of CD8, LAG3, programmed death-ligand 1 and anti-T-cell immunoglobulin and mucin-domain containing-3 at baseline. The pharmacokinetics profile of sabatolimab was consistent with the phase 1 study., Conclusions: Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types., Trial Registration Number: NCT02608268., Competing Interests: Competing interests: NM is the founder of and owns shares in MaxiVAX SA and is the CSO at MaxiVAX. C-CL reports an advisory role for AbbVie, Bayer, Blueprint Medicines, Bristol Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, Novartis and PharmaEngine; honoraria from Lilly, Novartis and Roche; and travel support from BeiGene, Daiichi Sankyo and Lilly. GC reports research funding from Merck and fees for advisory board from BMS, Merck, AstraZeneca, Novartis, Lilly, Pfizer, Roche, Exact Science, Daiichi Sankyo, GSK, Sanofi and Seagen. AS reports serving on an advisory board for BMS, Servier, Gilead, Pfizer, Eisai, Bayer and MSD (Merck Sharp & Dohme); consultancy for Arqule, Sanofi and Incyte; and participating in speaker’s bureaus for Takeda, BMS, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer and MSD. D-WK reports research funding to his institution from Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer-Ingelheim, Daiichi-Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Chong Keun Dang, Bridge BioTherapeutics, and GSK; and travel and accommodation support for advisory board meeting attendance from Amgen and Daiichi-Sankyo. DT reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Ipsen, Eisai and BMS; and consulting fees from Novartis, BMS and MSD. FSH reports receiving personal fees for serving on an advisory board for Surface, Compass Therapeutics, Apricity, Pionyr, 7 Hills Pharma, Torque, Bicara, Checkpoint Therapeutics, Bioentre, Iovance, Trillium, Amgen and Rheos; consultancy for Bristol-Myers Squibb, Merck, EMD Serono, Novartis, Sanofi, Pieris, Genentech/Roche, Catalym, Immunocore, Kairos, Eisai and Zumutor; serving as an advisor consultant for Aduro; and receiving other personal fees from Gossamer. FSH reports receiving grant support to institution from Bristol-Myers Squibb and Novartis; and having equity in Apricity, Pionyr, Torque, Bicara and Checkpoint Therapeutics. FSH holds issued patents #7250291, #9402905, #10279021 and #10106611 and pending patents #20100111973 (with royalties), #20170248603, #20160340407, #20160046716, #20140004112, #20170022275, #20170008962 and #20170343552, as well as a pending patent for Methods of Using Pembrolizumab and Trebananib. SW reports serving on an advisory board for Eisai, Bristol-Myers Squibb and Pierre Fabre (paid to institution). TD reports receiving grant support to institution from Lilly, MSD, Daiichi-Sankyo, Sumitomo Dainippon, Taiho, Novartis, Merck Biopharma, Janssen Pharma, Pfizer, BMS, AbbVie, Eisai, IQVIA, Chugai Pharma; consulting fees from Sumitomo Dainippon, Taiho, Takeda, Chugai Pharma, AbbVie, Bayer, Rakuten Medical, Otsuka Pharma, KAKEN Pharma, KYOWA KIRIN, SHIONOGI, PRA Health Science; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, Rakuten Medical, Ono Pharma, Daiichi-Sankyo, AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board for MSD, Daiichi-Sankyo, Amgen, Novartis, Boehringer Ingelheim, Janssen Pharma, AbbVie, Bayer, Astellas Pharma. CS-P was an employee of Novartis Institutes for BioMedical Research and holds patents on TIM-3 through Harvard/BWH and CoStim/Novartis. CS-P is employed by and has options in Larkspur Biosciences. SS is an employee of Novartis Institutes for BioMedical Research. SC is an NIBR employee and holds NVS stocks. AX has nothing to disclose. SG is an employee of Novartis Institutes for BioMedical Research. AP is an employee of Novartis Institutes for BioMedical Research., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)