Melanoma Drug Research Articles

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Aloysia Citrodora Essential Oil Inhibits Melanoma Cell Growth and Migration by Targeting HB-EGF-EGFR Signaling.

Patients diagnosed with melanoma have a poor prognosis due to regional invasion and metastases. The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is found in a subtype of melanoma with a poor prognosis and contributes to drug resistance. Aloysia citrodora essential oil (ALOC-EO) possesses an antitumor effect. Understanding signaling pathways that contribute to the antitumor of ALOC-EO is important to identify novel tumor types that can be targeted by ALOC-EO. Here, we investigated the effects of ALOC-EO on melanoma growth and tumor cell migration. ALOC-EO blocked melanoma growth in vitro and impaired primary tumor cell growth in vivo. Mechanistically, ALOC-EO blocked heparin-binding-epidermal growth factor (HB-EGF)-induced EGFR signaling and suppressed ERK1/2 phosphorylation. Myelosuppressive drugs upregulated HB-EGF and EGFR expression in melanoma cells. Cotreatment of myelosuppressive drugs with ALOC-EO improved the antitumor activity and inhibited the expression of matrix metalloproteinase-7 and -9 and a disintegrin and metalloproteinase domain-containing protein9. In summary, our study demonstrates that ALOC-EO blocks EGFR and ERK1/2 signaling, with preclinical efficacy as a monotherapy or in combination with myelosuppressive drugs in melanoma.

Polymorphisms at site 469 of B-RAF protein associated with skin melanoma may be correlated with dabrafenib resistance: An in silico study

Melanoma is a type of skin cancer. Numerous genes and their proteins are strongly associated with melanoma susceptibility. This study aims to use an in silico method to identify genetic variants in the melanoma susceptibility gene. The COSMIC database was queried for genes and cross-referenced with three environment–gene interaction databases (EGP, SeattleSNPs and CTD) to identify shared genes. The majority of approved skin melanoma drugs were found to act on the protein serine/threonine-protein kinase (B-RAF) encoded by the BRAF gene, which was also present in all three referenced databases. Comprehensive computational analysis was performed to predict deleterious genetic variants associated with skin melanoma, and the nsSNPs G469V and G469E were prioritized based on their predicted deleterious effects. Molecular dynamic simulation analysis of the B-RAF protein mutants G469V and G469E reveals that variations in the amino acid conformation at the drug binding site result in inconsistency in drug interaction. Additionally, this analysis showed that the G469V and G469E mutants have lower binding energy for dabrafenib than the wild type. The population with the highest frequency of each deleterious and pathogenic variant has been determined. The study's findings would support the development of more effective treatment strategies for skin melanoma. Communicated by Ramaswamy H. Sarma

Abstract LB261: BRAF inhibitor reprograms cancer-associated fibroblasts to elicit matrix remodeling and therapeutic escape in melanoma

Abstract The tumor stroma and its cellular components are known to play important roles in tumor resilience towards treatment but remain to be urgently characterized in melanoma targeted therapy. By performing a paired-analysis of melanoma tissue samples collected from the patients before and after combined BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) treatment, we discovered that the number of intratumoral cancer-associated fibroblasts (CAFs) increased significantly in BRAFi/MEKi-treated melanoma stroma comparing with the samples before the therapy. Those intratumoral CAFs exhibit increased amounts of nuclear β-catenin under BRAFi/MEKi therapy. Further studies show that BRAFi not only leads to increased β-catenin nuclear accumulation in CAFs and enhances their biological properties, suggesting BRAFi induces a new resistant phenotype in CAFs. In both in vitro and in vivo models, depleting β-catenin in CAFs abolishes their ability to elicit melanoma cell growth and drug resistance. BRAFi induces BRAF and CRAF dimerization and subsequently the activation of MEK/ERK signaling in CAFs, leading to the inactivation of the β-catenin destruction complex. RNA-Seq data reveals that nuclear β-catenin is a major regulator of CAF phenotype. We identify matricellular protein periostin (POSTN) as a downstream effector of β-catenin. In melanoma, POSTN is uniquely expressed in CAFs, and BRAFi can specifically upregulate POSTN production in CAFs but not in melanoma cells. Recombinant POSTN contributes to melanoma cell BRAFi/MEKi resistance and can compensate for the loss of β-catenin in CAFs. By reactivating ERK pathway in melanoma cells through PI3K/AKT signaling, POSTN compensates for the loss of β-catenin in CAFs in conferring melanoma cell BRAFi/MEKi resistance. In summary, our data reveal a novel resistance mechanism in melanoma that is elicited by BRAFi-induced non-canonical nuclear β-catenin signaling in CAFs and reveal POSTN as an important matrix target to eliminate BRAFi/MEKi resistance in melanoma. Citation Format: Tianyi Liu, Linli Zhou, Yuhang Zhang. BRAF inhibitor reprograms cancer-associated fibroblasts to elicit matrix remodeling and therapeutic escape in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB261.

Abstract 1171: Assessing Melanocortin 1 receptor as a target for metastatic melanoma drug delivery

Abstract In as little as six weeks, melanoma can turn life-threatening. Not only is melanoma a fast growing skin cancer, but its annual incidence rate is nearly 100,000 in the United States. Disease identified early can be cured by surgery, but metastatic melanoma is lethal. Despite the striking progress in treating metastatic melanoma using MAPK inhibitors and immune checkpoint inhibitors, improvements in objective response rate (<50%) and 5-yr survival (<30%) are critically needed. Melanocortin 1 receptor (MC1R), a G protein-coupled receptor, has been investigated as a potential target for drug delivery (e.g., peptide receptor radionuclide therapies, peptide-drug conjugates, etc.) to metastatic melanoma cells, as it is overexpressed in melanomas but largely absent in normal tissues. This study aims to further investigate the potential of MC1R as a target for drug delivery, by determining its expression in melanoma cancer cell lines, human melanoma biopsies, as well as normal tissue specimen. Bmax and MC1Rs per cell in five human melanoma cell lines (TXM13, TXM40, Sk-Mel-28, A375, and A2058) were calculated from saturation binding assays using synthetic MC1R ligand [125I]Nle-D-Phe-α-MSH (125I-NDP-α-MSH). An immunohistochemistry (IHC) staining protocol was developed using paraffin-embedded xenografts of TXM13, TXM40, Sk-Mel-28, A375, and A2058 human melanoma cells. IHC staining of MC1R was performed using human melanoma biopsy samples of stage III and IV metastatic melanoma obtained from University of Iowa Tissue Procurement Core Facility. MC1R-IHC was also performed on Caucasian North American normal tissue specimens including skin, muscle, pituitary gland, adrenal gland, cerebellum, and testis obtained from Amsbio. 125I-NDP-α-MSH binding assay results revealed positive staining in all melanoma cell lines, with the density of 2,762 receptors/cell in TXM13, 461 receptors/cell in Sk-Mel-28, 343 receptors/cell in TXM40, 164 receptors/cell in A375, and 93 receptors/cell in A2058. The IHC staining also demonstrated positive immunoreactivity against MC1R in stage III and IV human metastatic melanoma biopsy samples. Heterogenous expression of MC1R was found within the biopsy samples and among tumor biopsy samples, and the staining intensity fell within the range of the melanoma cancer cell line xenografts. Conversely, negative IHC staining of MC1R was found in normal tissue specimen, indicating that the expression of MC1R in normal tissues is largely absent. This study establishes an MC1R-IHC staining protocol optimized for clinical applications, and our data demonstrates high expression of MC1R in human melanoma biopsy samples as well as in melanoma cancer cell lines. The expression of MC1R in normal tissue specimens is largely absent. These results indicate that MC1R-targeted therapies, such as peptide receptor radionuclide therapies, are a promising alternative to current therapies for metastatic melanoma. Citation Format: Brenna Marks, Mengshi Li, Edwin Sagastume, Michael Schultz, Frances Johnson. Assessing Melanocortin 1 receptor as a target for metastatic melanoma drug delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1171.

Melanoma genomics: a state-of-the-art review of practical clinical applications.

Our collective understanding of melanoma genomics has rapidly expanded in the past decade, bringing great promise to patients affected with the most severe and aggressive cases of melanoma. In this review, we present the practical clinical impact of genetics and genomics on modern melanoma diagnosis and treatment. Characterization of somatic driver mutations, which can be used to distinguish different subtypes of melanoma such as nonacral cutaneous melanoma (NACM), desmoplastic melanoma (DM), acral melanoma (AM), mucosal melanoma (MM) and uveal melanoma (UM), has led to the development of many targeted therapies against these tumours. Although targeted therapies exist for certain mutations, such as BRAF and KIT, other genotypes respond to newer-generation immune therapies such as immune checkpoint inhibitors. Epigenetics also plays a critical role in melanoma pathogenesis and drug resistance, holding promise for new treatment avenues. In this review, special attention is placed on clinical trials and translational research, especially novel genomic tests aimed to benefit patients on an individualized level in the current emerging era of personalized therapy.

Прогностическое и предиктивное значение Т-клеток памяти в периферической крови у больных неоперабельной или метастатической меланомой

The generation, differentiation and maintenance of memory T-cells in the functionally optimal state is crucial for the effectiveness of the formation of antitumor immunity, including against the background of the use of immuno-oncological drugs in melanoma. The aim of the study was to test the hypothesis that the level of T-cells in the peripheral blood can serve as a marker of the therapy and survival of patients with melanoma effectiveness

Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications.

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets.

Development and Pilot Screen of Novel High Content Assay for Down Regulators of Expression of Heterogenous Nuclear Ribonuclear Protein H2.

Despite recent advances in melanoma drug discovery, the average overall survival of patients with late-stage metastatic melanoma is approximately 3 years, suggesting a need for new approaches and melanoma therapeutic targets. Previously we identified heterogeneous nuclear ribonucleoprotein H2 as a potential target of anti-melanoma compound 2155-14 (Palrasu et al., Cell Physiol Biochem 2019;53:656-686). In the present study, we endeavored to develop an assay to enable a high throughput screening campaign to identify drug-like molecules acting via down regulation of heterogeneous nuclear ribonucleoprotein H2 that can be used for melanoma therapy and research. We established a cell-based platform using metastatic melanoma cell line WM266-4 expressing hnRNPH2 conjugated with green fluorescent protein to enable assay development and screening. High Content Screening assay was developed and validated in 384 well plate format, followed by miniaturization to 1,536 well plate format. All plate-based QC parameters were acceptable: %CV = 6.7±0.3, S/B = 21±2.1, Z' = 0.75±0.04. Pilot screen of FDA-approved drug library (n=1,400 compounds) demonstrated hit rate of 0.5%. Two compounds demonstrated pharmacological response and were authenticated by western blot analysis. We developed a highly robust HTS-amenable high content screening assay capable of monitoring down regulation of hnRNPH2. This assay is thus capable of identifying authentic down regulators of hnRNPH1 and 2 in a large compound collection and, therefore, is amenable to a large-scale screening effort.

The Role of Senescent Cells in Acquired Drug Resistance and Secondary Cancer in BRAFi-Treated Melanoma.

Simple SummaryAdvances in melanoma treatment include v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors that target the predominant oncogenic mutation found in malignant melanoma. Despite initial success of the BRAF inhibitor (BRAFi) therapies, resistance and secondary cancer often occur. Mechanisms of resistance and secondary cancer rely on upregulation of pro-survival pathways that circumvent senescence. The repeated identification of a cellular senescent phenotype throughout melanoma progression demonstrates the contribution of senescent cells in resistance and secondary cancer development. Incorporating senotherapeutics in melanoma treatment may offer a novel approach for potentially improving clinical outcome.BRAF is the most common gene mutated in malignant melanoma, and predominately it is a missense mutation of codon 600 in the kinase domain. This oncogenic BRAF missense mutation results in constitutive activation of the mitogen-activate protein kinase (MAPK) pro-survival pathway. Several BRAF inhibitors (BRAFi) have been developed to specifically inhibit BRAFV600 mutations that improve melanoma survival, but resistance and secondary cancer often occur. Causal mechanisms of BRAFi-induced secondary cancer and resistance have been identified through upregulation of MAPK and alternate pro-survival pathways. In addition, overriding of cellular senescence is observed throughout the progression of disease from benign nevi to malignant melanoma. In this review, we discuss melanoma BRAF mutations, the genetic mechanism of BRAFi resistance, and the evidence supporting the role of senescent cells in melanoma disease progression, drug resistance and secondary cancer. We further highlight the potential benefit of targeting senescent cells with senotherapeutics as adjuvant therapy in combating melanoma.

Effects of Growth Hormone in Human Melanoma Drug Resistance

Melanoma, an extremely drug resistant form of cancer, displays elevated levels of growth hormone (GH) and growth hormone receptor (GHR) expression. We have described a GH dependent mechanism of chemoresistance in melanoma through a series of earlier studies. In GHR overexpressing human melanoma, GH action drives active drug efflux and phenotype switching by upregulating ATP-binding cassette transporters (ABC-transporters) and epithelial-to-mesenchymal transition (EMT) markers. Inhibition of GHR activation reverses these effects, increases drug retention, and sensitizes the melanoma cells to chemotherapy. GH action in melanoma also appears to drive drug sequestration in melanosomes as we present here. GH action was found to modulate the levels of melanocyte-inducing transcription factor (MITF), the master regulator of melanosome synthesis and melanoma. Additionally, MITF target gene levels and drug sequestering ABC transporter expression were also elevated by GH treatment in vitro and in vivo in mouse tumor xenografts. This was corroborated by in silico analyses of tumor databases. Furthermore, we observed a dose dependent increase in tyrosinase activity and melanogenesis in human melanoma cells with GH, in the presence of chemotherapy, which was suppressed by siRNA mediated GHR inhibition. Thus, we describe an array of molecular mechanisms by which GH drives chemoresistance in melanoma. Therefore, GHR inhibition combined with chemotherapy should lead to better tumor clearance and improve overall survival.

Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance.

Hypoxia and elevated extracellular acidification are prevalent features of solid tumors and they are often shown to facilitate cancer progression and drug resistance. In this review, we have compiled recent and most relevant research pertaining to the role of hypoxia and acidification in melanoma growth, invasiveness, and response to therapy. Melanoma represents a highly aggressive and heterogeneous type of skin cancer. Currently employed treatments, including BRAF V600E inhibitors and immune therapy, often are not effective due to a rapidly developing drug resistance. A variety of intracellular mechanisms impeding the treatment were discovered. However, the tumor microenvironment encompassing stromal and immune cells, extracellular matrix, and physicochemical conditions such as oxygen level or acidity, may also influence the therapy effectiveness. Hypoxia and acidification are able to reprogram the metabolism of melanoma cells, enhance their survival and invasiveness, as well as promote the immunosuppressive environment. For this reason, these physicochemical features of the melanoma niche and signaling pathways related to them emerge as potential therapeutic targets.

RTK Inhibitors in Melanoma: From Bench to Bedside.

Simple SummaryReceptor tyrosine kinases (RTKs) have long been demonstrated to play key roles in melanoma development. RTK activation requires dimerization and intracellular tyrosine trans-phosphorylation leading to downstream signaling pathways activation. As RTKs show different structures, mechanism of activation could differ. In this review, we will discuss the structure and specific mechanism of activation of each RTK, and its alteration associated with stage of the disease. Additionally, we summarize the effect of RTK inhibitors tested in preclinical and clinical melanoma studies indicating the reason, the reported results, and the rational approaches for combination strategies based on RTK inhibition in melanoma.MAPK (mitogen activated protein kinase) and PI3K/AKT (Phosphatidylinositol-3-Kinase and Protein Kinase B) pathways play a key role in melanoma progression and metastasis that are regulated by receptor tyrosine kinases (RTKs). Although RTKs are mutated in a small percentage of melanomas, several receptors were found up regulated/altered in various stages of melanoma initiation, progression, or metastasis. Targeting RTKs remains a significant challenge in melanoma, due to their variable expression across different melanoma stages of progression and among melanoma subtypes that consequently affect response to treatment and disease progression. In this review, we discuss in details the activation mechanism of several key RTKs: type III: c-KIT (mast/stem cell growth factor receptor); type I: EGFR (Epidermal growth factor receptor); type VIII: HGFR (hepatocyte growth factor receptor); type V: VEGFR (Vascular endothelial growth factor), structure variants, the function of their structural domains, and their alteration and its association with melanoma initiation and progression. Furthermore, several RTK inhibitors targeting the same receptor were tested alone or in combination with other therapies, yielding variable responses among different melanoma groups. Here, we classified RTK inhibitors by families and summarized all tested drugs in melanoma indicating the rationale behind the use of these drugs in each melanoma subgroups from preclinical studies to clinical trials with a specific focus on their purpose of treatment, resulted effect, and outcomes.

Melanoma models for the next generation of therapies.

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and exvivo and invitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies.

SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance.

Recent genomic and scRNA-seq analyses of melanoma demonstrated a lack of recurrent genetic drivers of metastasis, while identifying common transcriptional states correlating with invasion or drug resistance. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa:BRAFV600E;tp53-/- model, in which malignant progression is characterized by minimal genetic evolution. We undertook an overexpression-screen of 80 epigenetic/transcriptional regulators and found neural crest-mesenchyme developmental regulator SATB2 to accelerate aggressive melanoma development. Its overexpression induces invadopodia formation and invasion in zebrafish tumors and human melanoma cell lines. SATB2 binds and activates neural crest-regulators, including pdgfab and snai2. The transcriptional program induced by SATB2 overlaps with known MITFlowAXLhigh and AQP1+NGFR1high drug-resistant states and functionally drives enhanced tumor propagation and resistance to Vemurafenib in vivo. In summary, we show that melanoma transcriptional rewiring by SATB2 to a neural crest mesenchyme-like program can drive invasion and drug resistance in autochthonous tumors.

Ouabain Exhibited Strong Anticancer Effects in Melanoma Cells via Induction of Apoptosis, G2/M Phase Arrest, and Migration Inhibition.

BackgroundMalignant melanoma was characterized by insensitive chemotherapy, drug resistance, and high metastatic ability, which resulted in the main reason for the mortality among skin-related cancers. The current agents were not sufficient to improve the treatment status of melanoma patients, and it was still needed to develop new chemotherapeutic drugs for melanoma. Our study aimed to study the anticancer effects and potential mechanisms of ouabain on melanoma cells.MethodsThe inhibitory effects of ouabain were determined by CCK8 and colony formation assays, and the morphological changes of melanoma cells were observed by inverted microscope. The apoptosis induction and cell cycle distribution were detected by annexin V/PI double staining and PI staining, respectively. The expression of the biomarker proteins in apoptosis and G2/M phase were determined by Western blotting analysis. The effects of ouabain on the migration of melanoma cells were measured by transwell migration assay and wound closure analysis. The potential mechanisms of ouabain in melanoma cells were analyzed by transcriptome sequencing.ResultsOur present study demonstrated that ouabain exhibited strong inhibitory effects on cell proliferation and triggered dramatical morphological changes of melanoma cells. Moreover, ouabain induced significant apoptosis in A375 rather than SK-Mel-28 cells via upregulation of bax expression and downregulation of bcl-2 expression. Consistently, ouabain treatment induced cell cycle arrest at G2/M phase in both A375 and SK-Mel-28 cells via upregulation of cyclin B1 and downregulation of cdc2 and cdc25c. Importantly, ouabain suppressed the migration of A375 and SK-Mel-28 cells. Furthermore, the transcriptome sequencing demonstrated that p53 and MAPK signaling pathway might play important roles in the inhibitory effects of ouabain.ConclusionOur study revealed that ouabain exhibited dramatical anticancer effects, which provided a novel application for cardiac glycoside drugs in the clinical treatment of melanoma.

Screening and identification of potential biomarkers and therapeutic drugs in melanoma via integrated bioinformatics analysis.

Melanoma is a highly aggressive malignant skin tumor with a high rate of metastasis and mortality. In this study, a comprehensive bioinformatics analysis was used to clarify the hub genes and potential drugs. Download the GSE3189, GSE22301, and GSE35388 microarray datasets from the Gene Expression Omnibus (GEO), which contains a total of 33 normal samples and 67 melanoma samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) approach analyze DEGs based on the DAVID. Use STRING to construct protein-protein interaction network, and use MCODE and cytoHubba plug-ins in Cytoscape to perform module analysis and identified hub genes. Use Gene Expression Profile Interactive Analysis (GEPIA) to assess the prognosis of genes in tumors. Finally, use the Drug-Gene Interaction Database (DGIdb) to screen targeted drugs related to hub genes. A total of 140 overlapping DEGs were identified from the three microarray datasets, including 59 up-regulated DEGs and 81 down-regulated DEGs. GO enrichment analysis showed that these DEGs are mainly involved in the biological process such as positive regulation of gene expression, positive regulation of cell proliferation, positive regulation of MAP kinase activity, cell migration, and negative regulation of the apoptotic process. The cellular components are concentrated in the membrane, dendritic spine, the perinuclear region of cytoplasm, extracellular exosome, and membrane raft. Molecular functions include protein homodimerization activity, calmodulin-binding, transcription factor binding, protein binding, and cytoskeletal protein binding. KEGG pathway analysis shows that these DEGs are mainly related to protein digestion and absorption, PPAR signaling pathway, signaling pathways regulating stem cells' pluripotency, and Retinol metabolism. The 23 most closely related DEGs were identified from the PPI network and combined with the GEPIA prognostic analysis, CDH3, ESRP1, FGF2, GBP2, KCNN4, KIT, SEMA4D, and ZEB1 were selected as hub genes, which are considered to be associated with poor prognosis of melanoma closely related. Besides, ten related drugs that may have therapeutic effects on melanoma were also screened. These newly discovered genes and drugs provide new ideas for further research on melanoma.

Identification of novel biomarkers and candidate small-molecule drugs in cutaneous melanoma by comprehensive gene microarrays analysis.

Background: Melanoma is a pernicious skin cancer with high aggressiveness. This study aimed to identify potential novel biomarkers associated with the prognosis and pathogenesis of cutaneous melanoma and to explore new targeted drugs for melanoma. Methods: Two Gene Expression Omnibus (GEO) microarray datasets, GSE3189 and GSE7553 were combined to analyze the differentially expressed genes (DEGs). To better understand the DEGs in the melanoma pathogenesis, we performed gene enrichment analyses and established a protein-protein interaction network (PPI). The survival analyses for key genes were conducted based on the GEPIA platform. Finally, we mined the CMap database to explore potential small-molecule drugs to target the obtained DEGs. Results: In short, we identified 500 DEGs between cutaneous melanoma samples and normal samples. The PPI network was established with 349 nodes and 1251 edges. Signaling pathway analysis showed that these genes play a vital role in ECM-receptor interactions, the PPAR signaling pathway and pathways in cancer. Eight DEGs with a relatively high degree of connectivity (CDC45, CENPF, DTL, FANCI, GINS2, HJURP, TPX2 and TRIP13) were selected as hub-genes that remarkably correlated to a poor survival rate. Based on 500 DEGs, 20 small-molecule drugs that potentially target genes with abnormal expression in cutaneous melanoma were obtained from the CMap database. Among these compounds, we found that menadione has the greatest therapeutic value for melanoma. Conclusions: In conclusion, we identified the 8 candidate biomarkers and potential key signaling pathways in cutaneous melanoma through comprehensive microarray analyses. The identified candidate drugs have provided several directive significances for the synthesis medicine for melanoma.

Safety profile of drugs for advanced melanoma: A report based on 2008-2018 US Food and Drug Administration Data.

We describe the safety profiles of all drug classes used for the treatment of advanced melanoma from the US Food and Drug Administration Adverse Event Reporting System over 2008-2018. Adverse reactions reported in 25 900 pharmacovigilance cases are described for chemotherapies, immunomodulators, targeted therapies and immunotherapies. There was a sharp increase in the number of cases over time, with peaks associated with the launch of new treatments. The adverse reactions diversified over time; notably, skin (alopecias, dermatitis) and retinal disorders were frequently associated with targeted therapies and endocrine disorders (hypothalamus, thyroid and adrenal dysfunctions) with immunotherapies. Less well-known reactions were also detected, such as neuropsychiatric disorders with targeted therapies and gastrointestinal ulcers, pneumothorax and pleural effusions with immunotherapies. The findings highlight the need for various health professionals (including medical specialists or trained nurses) to enhance management of complications.

Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo.

Simple SummaryGrowth hormone (GH) action is strongly implicated in the progression and therapy resistance in several types of solid tumors which overexpress the GH receptor (GHR). The aim of our study was to characterize the effects of GH and its downstream effector insulin-like growth factor 1 (IGF-1) on melanoma using in vitro and in vivo models. We confirmed an IGF-1-independent role of elevated circulating GH in upregulating key mechanisms of therapy resistance and malignancy with analyses conducted at the molecular and cellular level. We identified that GH upregulates key mechanisms of therapy resistance and metastases in melanoma tumors in an IGF-1 dependent and independent manner by upregulating multidrug efflux pumps and EMT transcription factors. Our study reveals that GH action renders an intrinsic drug resistance phenotype to the melanoma tumors—a clinically crucial property of GH verifiable in other human cancers with GHR expression.Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.