Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Melanoma Res ; 34(4): 326-334, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38814728

RESUMO

Long follow-up time is needed for overall survival (OS) data to mature for early-stage melanoma. This retrospective study aimed to describe the relationships between OS and two intermediate endpoints - real-world recurrence-free survival (rwRFS) and real-world distant metastasis-free survival (rwDMFS) - for patients with stage IIB or IIC melanoma that was completely resected from 1 January 2008 to 31 December 2017, with follow-up to 31 December 2020. We used three different approaches to describe the relationships: estimates of correlation using Kendall τ rank correlation; comparisons of all-cause survival with/without recurrence or distant metastasis using adjusted Cox proportional hazard models; and landmark analyses of all-cause survival stratified by recurrence status at 1-5 years. During a 39-month median follow-up from surgical resection, 223/567 patients (39%) experienced recurrence, among whom 171/567 patients (30%) developed distant metastasis. Median OS from surgical resection was 117.6 months [95% confidence interval (CI), 104.7-not reached], median rwRFS was 49.8 months (95% CI, 39.6-61.0), and median rwDMFS was 70.9 months (95% CI, 58.4-89.1). We observed strong correlations between rwRFS and OS, and between rwDMFS and OS (Kendall τ of 0.73 and 0.82, respectively). Risk of death was significantly greater after recurrence (all-cause survival adjusted hazard ratio [HR], 7.48; 95% CI, 4.55-12.29) or distant metastasis (adjusted HR, 11.00; 95% CI, 6.92-17.49). Risk of death remained significantly elevated with recurrence or distant metastasis by landmark years 1, 3, and 5 after surgical resection. These findings support the use of recurrence/rwRFS and distant metastasis/rwDMFS as surrogate endpoints for OS after complete resection of stage IIB or IIC melanoma.


Assuntos
Melanoma , Recidiva Local de Neoplasia , Neoplasias Cutâneas , Humanos , Melanoma/cirurgia , Melanoma/mortalidade , Melanoma/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/mortalidade , Recidiva Local de Neoplasia/patologia , Idoso , Estadiamento de Neoplasias , Adulto , Intervalo Livre de Doença , Metástase Neoplásica
2.
J Clin Oncol ; 42(14): 1619-1624, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38452313

RESUMO

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716. Overall, 976 patients were randomly allocated to pembrolizumab (n = 487) or placebo (n = 489). As of January 4, 2023, median follow-up was 39.4 months (range, 26.0-51.4 months). The median DMFS was not reached in either treatment group, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (hazard ratio [HR], 0.59 [95% CI, 0.44 to 0.79]). The median RFS was not reached in either treatment group, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma. The safety profile of pembrolizumab was manageable and consistent with previous reports. These results continue to support the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma.


Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos , Melanoma , Estadiamento de Neoplasias , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Quimioterapia Adjuvante , Idoso , Método Duplo-Cego , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Antineoplásicos Imunológicos/uso terapêutico , Adulto , Intervalo Livre de Doença , Idoso de 80 Anos ou mais
3.
Adv Ther ; 40(7): 3038-3055, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37191852

RESUMO

INTRODUCTION: Pembrolizumab was approved in the US as adjuvant treatment of patients with stage IIB or IIC melanoma post-complete resection, based on prolonged recurrence-free survival vs. placebo in the Phase 3 KEYNOTE-716 trial. This study aimed to evaluate the cost-effectiveness of pembrolizumab vs. observation as adjuvant treatment of stage IIB or IIC melanoma from a US health sector perspective. METHODS: A Markov cohort model was constructed to simulate patient transitions among recurrence-free, locoregional recurrence, distant metastasis, and death. Transition probabilities from recurrence-free and locoregional recurrence were estimated via multistate parametric modeling based on patient-level data from an interim analysis (data cutoff date: 04-Jan-2022). Transition probabilities from distant metastasis were based on KEYNOTE-006 data and network meta-analysis. Costs were estimated in 2022 US dollars. Utilities were based on applying US value set to EQ-5D-5L data collected in trial and literature. RESULTS: Compared to observation, pembrolizumab increased total costs by $80,423 and provided gains of 1.17 quality-adjusted life years (QALYs) and 1.24 life years (LYs) over lifetime, resulting in incremental cost-effectiveness ratios of $68,736/QALY and $65,059/LY. The higher upfront costs of adjuvant treatment were largely offset by reductions in costs of subsequent treatment, downstream disease management, and terminal care, reflecting the lower risk of recurrence with pembrolizumab. Results were robust in one-way sensitivity and scenario analyses. At a $150,000/QALY threshold, pembrolizumab was cost-effective vs. observation in 73.9% of probabilistic simulations that considered parameter uncertainty. CONCLUSION: As an adjuvant treatment of stage IIB or IIC melanoma, pembrolizumab was estimated to reduce recurrence, extend patients' life and QALYs, and be cost-effective versus observation at a US willingness-to-pay threshold.


Assuntos
Análise de Custo-Efetividade , Melanoma , Humanos , Estados Unidos , Análise Custo-Benefício , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/tratamento farmacológico , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Melanoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida
5.
Pigment Cell Melanoma Res ; 36(2): 232-245, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36478412

RESUMO

Understanding pigmentation regulations taking into account the original skin color type is important to address pigmentary disorders. Biological models including adult melanocytes from different phenotypes allow to perform fine-tuned explorative studies and support discovery of treatments adapted to populations' skin color. However, technical challenges arise when trying to not only isolate but also amplify melanocytes from highly pigmented adult skin. To bypass the initial isolation and growth of cutaneous melanocytes, we harvested and expanded fibroblasts from light and dark skin donors and reprogrammed them into iPSC, which were then differentiated into melanocytes. The resulting melanocyte populations displayed high purity, genomic stability, and strong proliferative capacity, the latter being a critical parameter for dark skin cells. The iPSC-derived melanocyte strains expressed lineage-specific markers and could be successfully integrated into reconstructed skin equivalent models, revealing pigmentation status according to the native phenotype. In both monolayer cultures and 3D skin models, the induced melanocytes demonstrated responsiveness to promelanogenic stimuli. The data demonstrate that the iPSC-derived melanocytes with high proliferative capacity maintain their pigmentation genotype and phenotypic properties up to a proper integration into 3D skin equivalents, even for highly pigmented cells.


Assuntos
Células-Tronco Pluripotentes Induzidas , Pele , Melanócitos , Pigmentação da Pele , Diferenciação Celular
6.
Future Oncol ; 18(33): 3755-3767, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36346064

RESUMO

Aim: To describe clinical outcomes after complete surgical resection of stage IIB and IIC melanoma. Methods: Adult patients (n = 567) with stage IIB or IIC cutaneous melanoma initially diagnosed and completely resected from 2008-2017 were identified using data from a US community-based oncology network. Results: Median patient follow-up was 38.8 months from melanoma resection to death, last visit or data cut-off (31 December 2020). For stage IIB (n = 375; 66%), Kaplan-Meier median real-world recurrence-free survival (rwRFS) was 58.6 months (95% CI, 48.6-69.5). For stage IIC (n = 192; 34%), median rwRFS was 29.9 months (24.9-45.5). Overall, 44% of patients had melanoma recurrence or died; 30% developed distant metastases. Conclusion: Melanoma recurrence was common, highlighting the need for effective adjuvant therapy for stage IIB and IIC melanoma.


New treatments are now available that decrease tumor recurrence when administered after surgery to remove melanoma skin tumors that are graded as stage IIB or IIC (i.e., with no cancer spread to the local lymph nodes). We studied 567 'real-world' patients at clinics in the USA who had stage IIB or IIC melanoma tumors removed in 2008­2017, before these new postsurgical treatments were widely available, to evaluate their survival and tumor recurrence. We found that almost half of these patients (44%) had melanoma recurrence or had died, and a third (30%) had tumor spread beyond the original site, by the end of 2020. These findings highlight the need for more effective treatments after surgical removal of stage IIB and IIC melanoma.


Assuntos
Melanoma , Neoplasias Cutâneas , Adulto , Humanos , Melanoma/terapia , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/patologia , Terapia Combinada , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Melanoma Maligno Cutâneo
7.
Eur J Cancer ; 176: 207-217, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36202690

RESUMO

BACKGROUND: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported. METHODS: Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥12 to <18 years) Q3W or placebo for ≤17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥1 dose of treatment and completed ≥1 assessment. RESULTS: The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥80% for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms. CONCLUSIONS: HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma.


Assuntos
Melanoma , Qualidade de Vida , Humanos , Recidiva Local de Neoplasia , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Adjuvantes Imunológicos/uso terapêutico , Melanoma Maligno Cutâneo
8.
Lancet Oncol ; 23(11): 1378-1388, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36265502

RESUMO

BACKGROUND: Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up. METHODS: KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment. FINDINGS: Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [<1%]), rash (seven [1%] vs two [<1%]), autoimmune hepatitis (seven [1%] vs two [<1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported. INTERPRETATION: Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.


Assuntos
Melanoma , Neoplasias Cutâneas , Neoplasias Testiculares , Masculino , Humanos , Criança , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/cirurgia , Recidiva Local de Neoplasia/patologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
9.
J Invest Dermatol ; 142(7): 1882-1892.e5, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34883044

RESUMO

The upregulation of the adaptor protein NUMB triggers melanocytic differentiation from multipotent skin stem cells, which share many properties with aggressive melanoma cells. Although NUMB acts as a tumor suppressor in various human cancer types, little is known about its role in melanoma. In this study, we investigated the role of NUMB in melanoma progression and its regulatory mechanism. Analysis of The Cancer Genome Atlas melanoma datasets revealed that high NUMB expression in melanoma tissues correlates with improved patient survival. Moreover, NUMB expression is downregulated in metastatic melanoma cells. NUMB knockdown significantly increased the invasion potential of melanoma cells in a three-dimensional collagen matrix in vitro and in the lungs of a mouse model in vivo; it also significantly upregulated the expression of the NOTCH target gene CCNE. Previous studies suggested that Wnt signaling increases NUMB expression. By mimicking Wnt stimulation through glycogen synthase kinase-3 inhibition, we increased NUMB expression in melanoma cells. Furthermore, a glycogen synthase kinase-3 inhibitor reduced the invasion of melanoma cells in a NUMB-dependent manner. Together, our results suggest that NUMB suppresses invasion and metastasis in melanoma, potentially through its regulation of the NOTCH‒CCNE axis and that the inhibitors that upregulate NUMB can exert therapeutic effects in melanoma.


Assuntos
Melanoma , Proteínas de Membrana , Proteínas do Tecido Nervoso , Animais , Linhagem Celular Tumoral , Quinases da Glicogênio Sintase/metabolismo , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Via de Sinalização Wnt
10.
Cancer Res ; 81(20): 5230-5241, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34462276

RESUMO

Metastatic melanoma is challenging to clinically address. Although standard-of-care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSC) including high invasiveness, plasticity, and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi ± MEKi efficacy and ablated melanoma migration and invasion. Our data define LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell-like pathways hijacked by tumor cells. SIGNIFICANCE: This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance.


Assuntos
Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Melanoma/patologia , Crista Neural/patologia , Células-Tronco Neurais/patologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Crista Neural/efeitos dos fármacos , Crista Neural/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Prognóstico , Receptores de Ácidos Lisofosfatídicos/genética , Transcriptoma , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nat Commun ; 12(1): 346, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436641

RESUMO

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Linfócitos do Interstício Tumoral/imunologia , Mastócitos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/metabolismo , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
12.
J Invest Dermatol ; 138(1): 141-149, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28927893

RESUMO

Melanoma cells share many biological properties with neural crest stem cells. Here we show that the homeodomain transcription factor MSX1, which is significantly correlated with melanoma disease progression, reprograms melanocytes and melanoma cells toward a neural crest precursor-like state. MSX1-reprogrammed normal human melanocytes express the neural crest marker p75 and become multipotent. MSX1 induces a phenotypic switch in melanoma, which is characterized by an oncogenic transition from an E-cadherin-high nonmigratory state toward a ZEB1-high invasive state. ZEB1 up-regulation is responsible for the MSX1-induced migratory phenotype in melanoma cells. Depletion of MSX1 significantly inhibits melanoma metastasis in vivo. These results show that neural crest-like reprogramming achieved by a single factor is a critical process for melanoma progression.


Assuntos
Transformação Celular Neoplásica/patologia , Reprogramação Celular/fisiologia , Fator de Transcrição MSX1/fisiologia , Melanócitos/patologia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Derme/citologia , Derme/patologia , Progressão da Doença , Células HEK293 , Células-Tronco Embrionárias Humanas , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Fator de Transcrição MSX1/genética , Melanoma/mortalidade , Melanoma/secundário , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas do Tecido Nervoso/metabolismo , Crista Neural/fisiologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Cutâneas/mortalidade , Ensaios Antitumorais Modelo de Xenoenxerto , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
13.
Nat Commun ; 8(1): 607, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28928360

RESUMO

In melanoma, therapies with inhibitors to oncogenic BRAFV600E are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications.Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.


Assuntos
Antineoplásicos/uso terapêutico , Linfócitos B/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fator de Crescimento Insulin-Like I/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Sobrevivência Celular , Cisplatino/uso terapêutico , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Técnicas In Vitro , Melanoma/genética , Paclitaxel/uso terapêutico , Projetos Piloto , Proteínas Proto-Oncogênicas B-raf/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias Cutâneas/genética , Microambiente Tumoral
15.
Oncotarget ; 7(44): 71211-71222, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27655717

RESUMO

The discovery of activating BRAF mutations in approximately 50% of melanomas has led to the development of MAPK pathway inhibitors, which have transformed melanoma therapy. However, not all BRAF-V600E melanomas respond to MAPK inhibition. Therefore, it is important to understand why tumors with the same oncogenic driver have variable responses to MAPK inhibitors. Here, we show that concurrent loss of PTEN and activation of the Notch pathway is associated with poor response to the ERK inhibitor SCH772984, and that co-inhibition of Notch and ERK decreased viability in BRAF-V600E melanomas. Additionally, patients with low PTEN and Notch activation had significantly shorter progression free survival when treated with BRAF inhibitors. Our studies provide a rationale to further develop combination strategies with Notch antagonists to maximize the efficacy of MAPK inhibition in melanoma. Our findings should prompt the evaluation of combinations co-targeting MAPK/ERK and Notch as a strategy to improve current therapies and warrant further evaluation of co-occurrence of aberrant PTEN and Notch activation as predictive markers of response to therapy.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Indazóis/uso terapêutico , Melanoma/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Receptores Notch/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , Melanoma/genética , Melanoma/patologia , Camundongos , PTEN Fosfo-Hidrolase/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Receptores Notch/fisiologia
16.
J Cell Commun Signal ; 10(3): 191-196, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27553358

RESUMO

In the vertebrate embryo, melanocytes arise from the neural crest, migrate to and colonize the basal layer within the skin and skin appendages. Post-migratory melanocytes are securely attached to the basement membrane, and their morphology, growth, adhesion, and migration are under control of neighboring keratinocytes. Melanoma is a malignant tumor originated from melanocytes or their progenitor cells. During melanocyte transformation and melanoma progression, melanocytes lose their interactions with keratinocytes, resulting in uncontrolled proliferation and invasion of the malignant cells. Melanoma cells at the advanced stages often lack melanocytic features and resemble multipotent progenitors, which are a potential melanocyte reservoir in human skin. In this mini-review, we will summarize findings on cell-cell interactions that are responsible for normal melanocyte homeostasis, stem cell self-renewal, and differentiation. Our ultimate goal is to define molecules and pathways, which are essential for normal cell-cell interactions but deregulated in melanoma formation and progression.

17.
Methods Mol Biol ; 2015 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-26659798

RESUMO

Technological advances often dictate progress in cancer research. Melanoma research has been considerably influenced by implementation of novel techniques and has contributed to our understanding of the mechanism of tumor progression. The three-dimensional (3D) human skin reconstruct is an ideal model to dissect each step of melanoma development and progression. Reconstructed human skin consists of fibroblast-contracted collagen gels as a dermal compartment and a stratified epidermal compartment. The epidermis comprises keratinocytes and normal melanocytes or melanoma cells from different stages. Normal melanocytes in skin reconstructs remain singly distributed at the basement membrane within the basal layer of keratinocytes. The radial growth phase (RGP) melanoma cells grow as cell clusters in the epidermis. The vertical growth phase (VGP) melanoma cells invade the dermis of reconstructs. Metastatic melanoma cells aggressively invade deep into the dermis. Grafting melanoma skin reconstructs onto mice induces local tumor formation and metastatic foci in distant organs such as lungs. The growth patterns and the range of metastases reflect proliferation and metastatic capacity of the original tumors. Skin reconstruct as xenografts enable us to observe to which organs melanoma cells spread. In this chapter, we describe the usefulness of the model in studying not only melanocyte physiology but also pathophysiological conditions such as melanocyte transformation and melanoma progression. A better understanding of these processes will benefit the entire melanoma field.

18.
J Dermatol Sci ; 78(2): 143-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25818865

RESUMO

BACKGROUND: Melanocytes originate from the neural crest and migrate ventrally from the dorsal neural tube during embryogenesis. How human melanocytes locate at their suitable positions during embryogenesis, however, is unclear. Although a growing body of evidence indicates that melanocytes, melanoblasts, and melanocyte stem cells are closely related to hair follicles, little is known about volar skin. OBJECTIVE: The aim of this study was to observe skin development during human fetal period and clarify the site-specific migration process of human fetal sole melanocytes. METHODS: We obtained 4-mm punch biopsies from the scalp, back, abdomen, and right sole of 36 aborted fetuses (gestational age 12-21 weeks). We compared the migration process between hairly areas and volar areas by immunohistochemical staining. RESULTS: Immunohistochemical examination revealed that gp100 (HMB-45) sensitively detects human melanocytes in embryogenesis. Melanocytes were present at the epidermal base, where hair placodes/buds form at 12-15 weeks gestation. Fetal melanocytes in hair follicles are supplied from the epidermis. In volar skin, melanocytes originally localize only in the acrosyringium, where they migrate deeper into with gland development at 16-18 weeks gestation. Palmoplantar melanocyte migration and maturation processes differ considerably from those of the other hairy skin sites. CONCLUSION: Eccrine sweat glands seem to have a central role in the palmoplantar melanocyte migration process, similar to the role of hair follicles in hairy sites.


Assuntos
Movimento Celular , Glândulas Écrinas/embriologia , Epiderme/embriologia , Melanócitos/fisiologia , Parede Abdominal , Dorso , Glândulas Écrinas/citologia , Células Epidérmicas , Feto , , Idade Gestacional , Folículo Piloso/citologia , Folículo Piloso/embriologia , Humanos , Imuno-Histoquímica , Melanócitos/química , Antígenos Específicos de Melanoma/análise , Pigmentação/fisiologia , Couro Cabeludo , Antígeno gp100 de Melanoma
19.
Int J Cancer ; 137(6): 1503-8, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25754407

RESUMO

US28, a constitutively active G-protein-coupled receptor encoded by the human cytomegalovirus, leads to mechanistically unknown programmed cell death. Here we show that expression of wild-type US28 in human melanoma cells leads to apoptotic cell death via caspase 3 activation along with reduced cell proliferation. Reduced tumor growth upon US28 expression was observed in a xenograft mouse model. The signaling mute US28R129A showed a reduced antiproliferative effect. On evaluating different G-proteins coupled to US28 for signal transduction, Gα13 was identified as the main G-protein executing the apoptotic effect. Silencing of Gα13 but not Gαq resulted in a substantial increase in cell survival. Overexpression of Gα13 but not Gαq and their GTPase deficient forms Gα13Q226L and GαqQ209L, respectively, confirmed the requirement of Gα13 for US28 mediated cell death. Increasing expression of Gα13 alone induced cell death underscoring its relay function for US28 mediated decreased cell viability. Further reduced expression of Gα13 in melanoma cell lines isolated from advanced lesions and melanoma tissue was observed. These findings identified Gα13 as crucial for US28-induced cell death, substantiating that the effect of US28 on cell fate depends on preferred G-protein binding.


Assuntos
Morte Celular/fisiologia , Citomegalovirus/metabolismo , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Melanoma/metabolismo , Receptores de Quimiocinas/metabolismo , Proteínas Virais/metabolismo , Animais , Apoptose/fisiologia , Células COS , Caspase 3/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Chlorocebus aethiops , Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Camundongos , Células NIH 3T3 , Transdução de Sinais/genética
20.
J Invest Dermatol ; 135(6): 1521-1532, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25705850

RESUMO

Multipotent stem cells with neural crest-like properties have been identified in the dermis of human skin. These neural crest stem cell (NCSC)-like cells display self-renewal capacity and differentiate into neural crest derivatives, including epidermal pigment-producing melanocytes. NCSC-like cells share many properties with aggressive melanoma cells, such as high migratory capabilities and expression of the neural crest markers. However, little is known about which intrinsic or extrinsic signals determine the proliferation or differentiation of these neural crest-like stem cells. Here we show that, in NCSC-like cells, Notch signaling is highly activated, similar to melanoma cells. Inhibition of Notch signaling reduced the proliferation of NCSC-like cells, induced cell death, and downregulated noncanonical Wnt5a, suggesting that the Notch pathway contributes to the maintenance and motility of these stem cells. In three-dimensional skin reconstructs, canonical Wnt signaling promoted the differentiation of NCSC-like cells into melanocytes. This differentiation was triggered by the endogenous Notch inhibitor Numb, which is upregulated in the stem cells by Wnt7a derived from UV-irradiated keratinocytes. Together, these data reveal a cross talk between the two conserved developmental pathways in postnatal human skin, and highlight the role of the skin microenvironment in specifying the fate of stem cells.


Assuntos
Receptores Notch/metabolismo , Pele/metabolismo , Raios Ultravioleta , Proteínas Wnt/metabolismo , Diferenciação Celular , Linhagem da Célula , Sobrevivência Celular , Humanos , Queratinócitos/metabolismo , Lentivirus/genética , Melanócitos/citologia , Melanócitos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Pigmentação , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Fenômenos Fisiológicos da Pele , Células-Tronco/citologia , Proteína Wnt-5a , beta Catenina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...