Melanoma Therapy Research Articles

Targeted therapy or immunotherapy in BRAF-mutated metastatic melanoma: a Spanish center's decade of experience.

Targeted therapies and immunotherapy are currently considered the mainstay first-line treatment for advanced BRAF-mutated melanoma. However, the impact of treatment (targeted therapy and immunotherapy) and the prognostic factors are still not clear. Medical records of 140 patients diagnosed with advanced melanoma between 2011 and 2021 were retrospectively reviewed to extract demographic, BRAF status, treatment, performance status, and survival data. ORR, PFS, and OS were compared between patients diagnosed with advanced melanoma and treated with first-line IT or BRAF/MEKi. The prognostic factors were assessed using Cox regression models. In all patients and those treated with immunotherapy, we did not find any effect of BRAF status on ORR, PFS, or OS. In patients with BRAF-mutated melanoma, ORR was 43.8% vs. 70% (P=0.04), PFS was 19.2 vs. 11.5 months (p=0.22), and OS was 33.4 vs. 16.4 months for the immunotherapy and targeted therapy groups, respectively (P=0.04). ECOG, presence of brain metastases, and high LDH level from initiation of first-line treatment were all associated with differences in PFS and OS. Patients with advanced BRAF-mutated melanoma treated with first-line immunotherapy had a significantly longer PFS and OS than those treated with first-line BRAF/MEKi; however, first-line BRAF/MEKi treatment had a significantly higher ORR than first-line immunotherapy.

Long-term survival with systemic therapy in the last decade: Can melanoma be cured?

Immune checkpoint inhibitors have been shown to prolong survival of patients with several types of cancer, and the finding was first established in melanoma. Previously, systemic therapy for advanced melanoma aimed only at tumor control and palliation of symptoms. However, in recent years, some patients who received systemic therapy have achieved a complete response and survived without continuous treatment for more than several years. This review discusses the long-term survival rates achieved with currently used systemic therapies and their future perspectives. Long-term survival is currently most likely to be achieved with the use of the standard-dose combination of nivolumab plus ipilimumab, however, this regimen is associated with a high frequency of serious or persistent immune-related adverse events. Several new anti-PD-1-based combination therapies with a better risk-benefit balance are currently under development. Although the acral and mucosal subtypes tend to be less responsive to immune checkpoint inhibitors, anti-PD-1-based combination therapy should continue to be investigated for these subtypes owing to its potential for better long-term survival. With the development of efficacious immunotherapy and targeted therapy, it is important to determine the optimal duration of systemic therapy to avoid unnecessary health and financial burdens as well as to improve efforts to support long-term cancer survivors. As the goal of systemic therapy shifts from tumor control to long-term survival, in future clinical trials, long-term clinical outcomes should be evaluated to assess the benefits of novel agents.

Review: Are moles senescent?

Melanocytic nevi (skin moles) have been regarded as a valuable example of cell senescence occurring invivo. However, a study of induced nevi in a mouse model reported that the nevi were arrested by cell interactions rather than a cell-autonomous process like senescence, and that size distributions of cell nests within nevi could not be accounted for by a stochastic model of oncogene-induced senescence. Moreover, others reported that some molecular markers used to identify cell senescence in human nevi are also found in melanoma cells-not senescent. It has thus been questioned whether nevi really are senescent, with potential implications for melanoma diagnosis and therapy. Here I review these areas, along with the genetic, biological, and molecular evidence supporting senescence in nevi. In conclusion, there is strong evidence that cells of acquired human benign (banal) nevi are very largely senescent, though some must contain a minor non-senescent cell subpopulation. There is also persuasive evidence that this senescence is primarily induced by dysfunctional telomeres rather than directly oncogene-induced.

Synergistic anticancer effect of Pistacia lentiscus essential oils and 5-Fluorouracil co-loaded onto biodegradable nanofibers against melanoma and breast cancer

Chemoresistance and severe toxicities represent major drawbacks of chemotherapy. Natural extracts, including the essential oils of Pistacia lentiscus (PLEO), exhibit substantial anticancer and anti-inflammatory activities where different cancers are reported to dramatically recess following targeting with PLEO. PLEO has promising antimicrobial, anticancer, and anti-inflammatory properties. However, the therapeutic properties of PLEO are restricted by limited stability, bioavailability, and targeting ability. PLEO nanoformulation can maximize their physicochemical and therapeutic properties, overcoming their shortcomings. Hence, PLEO was extracted and its chemical composition was determined by GC–MS. PLEO and 5-Fluorouracil (5FU) were electrospun into poly-ε-caprolactone nanofibers (PCL-NFs), of 290.71 nm to 680.95 nm diameter, to investigate their anticancer and potential synergistic activities against triple-negative breast cancer cells (MDA-MB-231), human adenocarcinoma breast cancer cells (MCF-7), and human skin melanoma cell line (A375). The prepared nanofibers (NFs) showed enhanced thermal stability and remarkable physical integrity and tensile strength. Biodegradability studies showed prolonged stability over 42 days, supporting the NFs use as a localized therapy of breast tissues (postmastectomy) or melanoma. Release studies revealed sustainable release behaviors over 168 h, with higher released amounts of 5FU and PLEO at pH 5.4, indicating higher targeting abilities towards cancer tissues. NFs loaded with PLEO showed strong antioxidant properties. Finally, NFs loaded with either PLEO or 5FU depicted greater anticancer activities compared to free compounds. The highest anticancer activities were observed with NFs co-loaded with PLEO and 5FU. The developed 5FU-PLEO-PCL-NFs hold potential as a local treatment of breast cancer tissues (post-mastectomy) and melanoma to minimize their possible recurrence.Graphical

A versatile theranostic magnetic polydopamine iron oxide NIR laser-responsive nanosystem containing doxorubicin for chemo-photothermal therapy of melanoma

Theranostics nanoparticles (NPs) have recently received much attention in cancer imaging and treatment. This study aimed to develop a multifunctional nanosystem for the targeted delivery of photothermal and chemotherapy agents. Fe3O4 NPs were modified with polydopamine, bovine serum albumin, and loaded with DOX via a thermal-cleavable Azo linker (Fe3O4@PDA@BSA-DOX). The size of Fe3O4@PDA@BSA NPs was approximately 98 nm under the desired conditions. Because of the ability of Fe3O4 and PDA to convert light into heat, the temperature of Fe3O4@PDA@BSA NPs increased to approximately 47 °C within 10 min when exposed to an 808 nm NIR laser with a power density of 1.5 W/cm2. The heat generated by the NIR laser leads to the breaking of AZO linker and drug release. In vivo and in vitro results demonstrated that prepared NPs under laser irradiation successfully eradicated tumor cells without any significant toxicity effect. Moreover, the Fe3O4@PDA@BSA NPs exhibited the potential to function as a contrasting agent. These NPs could accumulate in tumors with the help of an external magnet, resulting in a significant enhancement in the quality of magnetic resonance imaging (MRI). The prepared novel multifunctional NPs seem to be an efficient system for imaging and combination therapy in melanoma.

Interferon alpha 2b or Mitomycin-C as Adjuvant Therapy of Pigmented Conjunctival Malignancy : A Literature Review

Abstract
 Introduction & Objectives : To compare the efficacy and safety between Mitomycin C (MMC) and Interferon alpha-2b (IFN-α2b) eye drops as adjuvant therapy for conjunctival melanoma.
 Methods : Literature searching was conducted using PubMed, ScienceDirect, and Google Scholar. All studies that met the inclusion and exclusion criteria were categorized based on the level of evidence. The data of patients demographics, staging of disease, type of treatments, and outcomes of this review including local control rate, side effect, and recurrence and/or metastases were also reported.
 Results : From twelve articles, topical adjuvant chemotherapy with MMC and IFN α-2b showed favourable complete remission rate. Local control (complete remission) of IFN α-2b group is 46%, while in MMC group is 57%. The most side effect of MMC group were severe corneal-conjunctival irritation and corneal defect, while the IFN α-2b group showed mild side effect. Recurrency rate of IFN α-2b group and MMC group both is 35%. Metastases case of IFN α-2b group is 3.8%, while none of cases from MMC group metastases.
 Conclusion : Topical adjuvant chemotherapy with MMC and IFN α-2b showed favourable local control rate even though the recurrency rate also relatively high. Both medications showed promising results to reduce residual tumor size after wide excision surgery, preserving eye so reduce the chance of exenteration in various stages. It is important to consider adjuvant therapy following wide excision surgery as the first line treatment.

Immune checkpoint inhibitors in metastatic melanoma therapy (Review).

An increase in the incidence of melanoma has been observed in recent decades, which poses a significant challenge due to its poor prognosis in the advanced and metastatic stages. Previously, chemotherapy and high doses of interleukin-2 were available treatments for melanoma; however, they offered limited survival benefits and were associated with severe toxicities. The treatment of metastatic melanoma has been transformed by new developments in immunotherapy. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligand, PDL-1, have emerged as promising therapeutic options. Commonly used ICIs, such as ipilimumab, nivolumab and pembrolizumab, have been found to be associated with an improved median overall survival, recurrence-free survival and response rates compared to traditional chemotherapies. Combination therapies involving different types of ICIs, such as anti-PD1 with anti-CTLA-4, have further enhanced the overall survival and response rates by targeting various phases of T-cell activation. Additionally, the development of novel biomarkers has facilitated the assessment of responses to ICI therapy, with tissue and serum-based prognostic and predictive biomarkers now available. The increased response observed with ICIs also provides potential for immune-related adverse effects on various organ systems. Further research is required to evaluate the efficacy and safety of various combinations of ICIs, while ongoing clinical trials explore the potential of newer ICIs. Concerns regarding the development of resistance to ICIs also warrant attention. The present review summarizes and discusses the advent of ICIs with a marked significant breakthrough in the treatment of metastatic melanoma, providing improved outcomes compared to traditional therapies.

Therapeutic Strategies in BRAF V600 Wild-Type Cutaneous Melanoma.

There have been many recent advances in melanoma therapy. While 50% of melanomas have a BRAF mutation and are a target for BRAF inhibitors, the remaining 50% are BRAF wild-type. Immune checkpoint inhibitors targeting PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and lymphocyte activated gene-3 (Lag-3) are all approved for the treatment of patients with advanced BRAF wild-type melanoma; however, treatment of this patient population following initial immune checkpoint blockade is a current therapeutic challenge given the lack of other efficacious options. Here, we briefly review available US FDA-approved therapies for BRAF wild-type melanoma and focus on developing treatment avenues for this heterogeneous group of patients. We review the basics of genomic features of both BRAF mutant and BRAF wild-type melanoma as well as efforts underway to develop new targeted therapies involving the mitogen-activated protein kinase (MAPK) pathway for patients with BRAF wild-type tumors. We then focus on novel immunotherapies, including developing checkpoint inhibitors and agonists, cytokine therapies, oncolytic viruses and tumor-infiltrating lymphocytes, all of which represent potential therapeutic avenues for patients with BRAF wild-type melanoma who progress on currently approved immune checkpoint inhibitors.

A Review of Current and Pipeline Drugs for Treatment of Melanoma.

Malignant melanoma is the most aggressive form of skin cancer. Standard treatment options include surgery, radiation therapy, systemic chemotherapy, targeted therapy, and immunotherapy. Combining these modalities often yields better responses. Surgery is suitable for localized cases, sometimes involving lymph node dissection and biopsy, to assess the spread of the disease. Radiation therapy may be sometimes used as a standalone treatment or following surgical excision. Systemic chemotherapy, while having low response rates, is utilized as part of combination treatments or when other methods fail. The development of resistance to systemic chemotherapies and associated side effects have prompted further research and clinical trials for novel approaches. In the case of advanced-stage melanoma, a comprehensive approach may be necessary, incorporating targeted therapies and immunotherapies that demonstrate significant antitumor activity. Targeted therapies, including inhibitors targeting BRAF, MEK, c-KIT, and NRAS, are designed to block the specific molecules responsible for tumor growth. These therapies show promise, particularly in patients with corresponding mutations. Combination therapy, including BRAF and MEK inhibitors, has been evidenced to improve progression-free survival; however, concerns about resistance and cutaneous toxicities highlight the need for close monitoring. Immunotherapies, leveraging tumor-infiltrating lymphocytes and CAR T cells, enhance immune responses. Lifileucel, an FDA-approved tumor-infiltrating lymphocyte therapy, has demonstrated improved response rates in advanced-stage melanoma. Ongoing trials continue to explore the efficacy of CAR T-cell therapy for advanced melanoma. Checkpoint inhibitors targeting CTLA-4 and PD-1 have enhanced outcomes. Emerging IL-2 therapies boost dendritic cells, enhancing anticancer immunity. Oncolytic virus therapy, approved for advanced melanoma, augments treatment efficacy in combination approaches. While immunotherapy has significantly advanced melanoma treatment, its success varies, prompting research into new drugs and factors influencing outcomes. This review provides insights into current melanoma treatments and recent therapeutic advances.

Salmonella-mediated methionine deprivation drives immune activation and enhances immune checkpoint blockade therapy in melanoma

BackgroundAlthough immune checkpoint inhibitor (ICI)-based therapy is advantageous for patients with advanced melanoma, resistance and relapse are frequent. Thus, it is crucial to identify effective drug combinations and develop new...

Metabolic Profiling to Assess Response to Targeted and Immune Therapy in Melanoma.

There is currently no consensus to determine which advanced melanoma patients will benefit from targeted therapy, immunotherapy, or a combination of both, highlighting the critical need to identify early-response biomarkers to advanced melanoma therapy. The goal of this review is to provide scientific rationale to highlight the potential role of metabolic imaging to assess response to targeted and/or immune therapy in melanoma cancer. For that purpose, a brief overview of current melanoma treatments is provided. Then, current knowledge with respect to melanoma metabolism is described with an emphasis on major crosstalks between melanoma cell metabolism and signaling pathways involved in BRAF-targeted therapy as well as in immune checkpoint inhibition therapies. Finally, preclinical and clinical studies using metabolic imaging and/or profiling to assess response to melanoma treatment are summarized with a particular focus on PET (Positron Emission Tomography) imaging and 13C-MRS (Magnetic Resonance Spectroscopy) methods.

Pembrolizumab Versus High-Dose Interferon-α2b as Adjuvant Therapy for Pediatric Melanoma: A Retrospective Study.

Pembrolizumab is well-tolerated in pediatric patients with advanced tumors, consistent with results in adults. However, information on the safety and efficacy of adjuvant pembrolizumab in children and adolescents with melanoma is lacking. To compare pembrolizumab versus high-dose interferon-α2b (HDI) as adjuvant therapy in pediatric patients with melanoma. We performed a retrospective study of pediatric patients diagnosed with melanoma between January 2008 and April 2022. Relapse-free survival (RFS) and the 1-year RFS rate were compared between patients receiving adjuvant pembrolizumab or HDI. Seventy-five pediatric patients with melanoma were screened from a database of 6,013 patients. Twenty-four patients were finally enrolled, of whom 9 received pembrolizumab and 15 received HDI as adjuvant therapy. By August 31, 2022, the median follow-up times were 23.6 months and 98.7 months in the pembrolizumab and HDI groups, respectively. There was no significant difference in median RFS between two groups (not reached versus 38.7 months, P = 0.11). The median overall survival was not reached in either group. The 1-year RFS rates were 88.9% and 66.7% in the pembrolizumab and HDI groups, respectively. All adverse events in the pembrolizumab group were grade 1 or 2, but grade 3-5 adverse events occurred in two (13%) patients receiving HDI. RFS was similar in pediatric patients with melanoma receiving adjuvant pembrolizumab or HDI, but pembrolizumab was associated with a reduced risk of recurrence and a more favorable safety profile. However, due to the small sample size and differences in follow-up time, larger and prospective studies are still warranted to explore better adjuvant therapies for pediatric melanoma.

The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma.

Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in patients with clinically occult disease. Since the advent of new systemic therapies, its role in melanoma has been extensively debated over the last years. In this article, three possible scenarios are discussed, considering the SLNB impact on the management of melanoma patients. First, pT1b and pT2a patients with negative SLNB (stages IA and IB) and those with positive SLNB (stage IIIA) would all not benefit from adjuvant treatment. Therefore, SLNB might be avoided in these categories of patients. Second, in IIB and IIC, melanoma patients are already candidates for adjuvant treatment; therefore, SLNB in patients with T3b, T4a, or T4b melanoma would not change treatment decisions. On the other end of the spectrum, patients with pT2b and pT3a melanomas (clinical stage IIA) represent the only two groups whose management would be significantly affected by the SLNB status, being adjuvant therapy only indicated for SLN-positive patients. Further studies are needed to investigate which melanoma patient deserves SLNB.

The Effect of Non-Overlapping Somatic Mutations in BRAF, NRAS, NF1, or CKIT on the Incidence and Outcome of Brain Metastases during Immune Checkpoint Inhibitor Therapy of Metastatic Melanoma

The Effect of Non-Overlapping Somatic Mutations in BRAF, NRAS, NF1, or CKIT on the Incidence and Outcome of Brain Metastases during Immune Checkpoint Inhibitor Therapy of Metastatic Melanoma

Engineered in vivo and in vitro tumor model recapitulates vasculogenic mimicry signatures in melanoma.

Vasculogenic mimicry (VM) describes a process by which tumor cells formed a novel microcirculation pattern in an endothelial cell-free manner. Clinically, VM is associated with aggressive phenotype and poor patient survival. However, the current models for investigating VM include 2D monolayer cultures, Matrigel-based cultures, and animal models, each of which has limitations. Matrigel-based models often exhibit batch-to-batch variations, while in vivo tumor models currently produce insufficient amounts of VM. There is currently no suitable tumor model to discover new therapeutic targets against VM. Herein, we establish an extracellular matrix (ECM)-based engineered tumor model in vivo and in vitro. In this study, we demonstrate that matrix proteins enhanced the VM formation in the engineered xenograft model. Furthermore, we also investigated the role of collagen/fibronectin (FN) in melanoma progression and VM formation. Compared with cells cultured on TCPS plates, the B16F10 cells cultured on collagen/FN coated plates showed increased proliferation and stemness, and significantly enhanced invasion and formation of VM networks. Molecular mechanism analysis showed that Integrin/VE-cadherin/EphA2/PI3K/MMP-2 signaling pathways are responsible for VM formation. Our results indicate that collagen/FN matrix plays an important role in VM formation in melanoma, suggesting that ECM protein is a potential therapeutic target for anti-VM therapy for melanoma.

Machine Learning-Assisted Optimization of Drug Combinations in Zeolite-Based Delivery Systems for Melanoma Therapy.

Two independent artificial neural network (ANN) models were used to determine the optimal drug combination of zeolite-based delivery systems (ZDS) for cancer therapy. The systems were based on the NaY zeolite using silver (Ag+) and 5-fluorouracil (5-FU) as antimicrobial and antineoplastic agents. Different ZDS samples were prepared, and their characterization indicates the successful incorporation of both pharmacologically active species without any relevant changes to the zeolite structure. Silver acts as a counterion of the negative framework, and 5-FU retains its molecular integrity. The data from the A375 cell viability assays, involving ZDS samples (solid phase), 5-FU, and Ag+ aqueous solutions (liquid phase), were used to train two independent machine learning (ML) models. Both models exhibited a high level of accuracy in predicting the experimental cell viability results, allowing the development of a novel protocol for virtual cell viability assays. The findings suggest that the incorporation of both Ag and 5-FU into the zeolite structure significantly potentiates their anticancer activity when compared to that of the liquid phase. Additionally, two optimal AgY/5-FU@Y ratios were proposed to achieve the best cell viability outcomes. The ZDS also exhibited significant efficacy against Escherichia coli (E.coli) and Staphylococcus aureus (S. aureus); the predicted combination ratio is also effective against S.aureus, underscoring the potential of this approach as a therapeutic option for cancer-associated bacterial infections.

Augmenting MEK inhibitor efficacy in BRAF wild-type melanoma: synergistic effects of disulfiram combination therapy

BackgroundMEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was constitutively activated due to mutations in NRAS or NF-1. Thus, novel combinations are needed to increase the efficacy and duration of response to MEKi in BRAF WT melanoma. Disulfiram and its metabolite diethyldithiocarbamate are known to have antitumor effects related to cellular stress, and induction of endoplasmic reticulum (ER) stress was found to synergize with MEK inhibitors in NRAS-mutated melanoma cells. Therefore, we investigated the combination of both therapeutics to test their effects on BRAF-WT melanoma cells and compared them with monotherapy using the MEKi trametinib.MethodsThe effects of combined therapy with disulfiram or its metabolite diethyldithiocarbamate and the MEKi trametinib were evaluated in a series of BRAF-WT melanoma cell lines by measuring cell viability and apoptosis induction. Cytotoxicity was additionally assessed in 3D spheroids, ex vivo melanoma slice cultures, and in vivo xenograft mouse models. The response of melanoma cells to treatment was studied at the RNA and protein levels to decipher the mode of action. Intracellular and intratumoral copper measurements were performed to investigate the role of copper ions in the antitumor cytotoxicity of disulfiram and its combination with the MEKi.ResultsDiethyldithiocarbamate enhanced trametinib-induced cytotoxicity and apoptosis induction in 2D and 3D melanoma culture models. Mechanistically, copper-dependent induction of oxidative stress and ER stress led to Janus kinase (JNK)-mediated apoptosis in melanoma cells. This mechanism was also detectable in patient-derived xenograft melanoma models and resulted in a significantly improved therapeutic effect compared to monotherapy with the MEKi trametinib.ConclusionsDisulfiram and its metabolite represent an attractive pharmaceutical approach to induce ER stress in melanoma cells that potentiates the antitumor effect of MEK inhibition and may be an interesting candidate for combination therapy of BRAF WT melanoma.

Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β and interleukin-6: biochemical implications in cardio-immuno-oncology.

Immune checkpoint blockade in monotherapy or combinatorial regimens with chemotherapy or radiotherapy have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) antibody, Relatlimab, has been approved by FDA in combination with Nivolumab for metastatic melanoma therapy. Moreover, Atezolizumab is actually under study in association with Ipilimumab for therapy of metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies could expose patients to more adverse cardiovascular events. Human cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, troponin-T, BNP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Mitochondrial functions were studied in cardiomyocyte cell lysates through quantification of intracellular Ca++, ATP content and NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) levels. Histone deacetylases type 4 (HDAC-4) protein levels were also determined in cardiomyocyte cell lysates to study potential epigenetic changes induced by immunotherapy regimens. Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. HDAC4 and intracellular Ca++ levels were increased, instead ATP content and Ndufs1 were reduced in myocardial cell lysates (p < 0.001 vs. untreated cells). Troponin-T, BNP, NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy compared to monotherapy regimen. NLRP3 expression, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies. Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.

Efficacy and safety of ‘Second Adjuvant’ therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy

BackgroundAnti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. BRAFV600-mutated (BRAFmut) melanoma patients who recur with isolated disease following adjuvant therapy may be suitable for ‘second adjuvant' treatment after local therapy. We sought to examine the efficacy and safety of ‘second adjuvant’ BRAF/MEKi. Patients and methodsPatients with BRAFmut melanoma treated with adjuvant PD-1 based immunotherapy who recurred, underwent definitive local therapy and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres (second adjuvant group). Demographics, disease and treatment characteristics and outcome data were examined. Outcomes were compared to BRAFmut patients who did not receive ‘second adjuvant’ therapy (no second adjuvant group). Results73 patients were included; 61 who received ‘second adjuvant’ therapy and 12 who did not. Most initially recurred on PD-1 therapy (66%). There were no differences in characteristics between groups. 92% of second adjuvant group received dabrafenib and trametinib and median duration of therapy was 11.8 months (0.4, 34.5). 72% required dose adjustments, 23% had grade 3 + toxicity and 38% permanently discontinued drug due to toxicity. After median 26.1 months (1.9, 56.3) follow-up, recurrence-free survival (RFS) was improved in second adjuvant group versus no second adjuvant group (median 30.8 vs 4 months, HR 0.35; p = 0.014), largely driven by a delay in early recurrence, with no difference in overall survival (p = 0.59). ConclusionThis is the first study examining outcomes of ‘second adjuvant’ targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes.

SIRT7 sustains tumor development and radioresistance by repressing endoplasmic reticulum stress-induced apoptosis in cutaneous melanoma

Cutaneous melanoma is one of the most malignant human tumors and possesses strong resistance to radiotherapy. However, the mechanisms contribute to such radioresistance of melanoma is unclear. In this study, SIRT7 is identified to be higher-expressed in melanoma and positively correlated with melanoma staging. Under ionizing radiation (IR)-treatment condition, loss of SIRT7 compromised the survivability of melanoma cells showed by decreased proliferation, colony formation, migration, but enhancing apoptosis. Transcriptomic sequencing analysis indicated the apoptosis induced after SIRT7 knockdown is tightly related with the induction of endoplasmic reticulum stress (ER stress) by IR treatment. Loss of SIRT7 enhanced EIF2α acetylation and activated its phosphorylation to induce the expression of ER stress proteins including DDIT3, XBP1 and GRP78, among which DDIT3 is responsible for apoptosis induction. SIRT7 depletion enriched ER stress-activated transcription factor ATF4 at the promoter region of DDIT3 gene to transactivate its expression and induces apoptotic cascade in both mock- and IR-treatment conditions. Consistently, SIRT7 is highly upregulated in radioresistant melanoma cell strain and still modulates the ER-stress responsive genes to maintain the homeostasis of melanoma. Collectively, SIRT7 negatively regulates ER stress-activated apoptosis to enhance the survivability of melanoma cells in both non-IR- and IR-treatment conditions. Our study highlights the role of SIRT7 in repressing ER stress and the following apoptosis to sustain tumor development and mediate radioresistance in melanoma, which may suggest a novel intervention target for melanoma therapy.