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2.
Anticancer Res ; 40(4): 2157-2163, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234909

RESUMEN

BACKGROUND/AIM: There is a lack of quality biomarkers of survival for patients with metastatic melanoma treated with immunotherapy. Although the baseline level of S100 has prognostic value, its role during/after therapy in survival is unclear. PATIENTS AND METHODS: We evaluated patients with metastatic melanoma treated with pembrolizumab with the goal of analysing the relationship between a relative change in S100 level at 12 weeks of immunotherapy and survival. RESULTS: Patients with a relative change in S100 level >145% at 12 weeks of immunotherapy had significantly shorter progression-free (5.1 vs. 18.5 months, p≤0.0001) and overall survival (5.7 vs. 26.3 months, p<0.0001), further confirmed on multivariate analysis with hazard ratio of 32.25 (95% confidence interval=4.78-217.6, p=0.0004) for overall survival. CONCLUSION: A relative change in S100 level might be useful as a more precise biomarker of survival for patients with metastatic melanoma treated with pembrolizumab.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores de Tumor/análisis , Melanoma/tratamiento farmacológico , Proteínas S100/análisis , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología
4.
Medicine (Baltimore) ; 99(10): e19439, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32150095

RESUMEN

INTRODUCTION: Immune checkpoint inhibitors (ICIs) represent an important advance in the treatment of melanoma. ICIs may induce autoimmune phenomena caused by concurrent activation of the immune system against normal cells. During the last years, cases of musculoskeletal side effects, especially immune-mediated arthritis (IA), have been increasingly reported. PATIENT CONCERNS: We present a 59-year-old woman, who was treated with pembrolizumab for a relapsed BRAF V600E mutated cutaneous malignant melanoma. The patient presented with right knee arthritis on week 30. DIAGNOSIS: The erythrocyte sedimentation rate and serum C-reactive protein levels were elevated, while rheumatoid factor and anti-cyclic citrullinated peptide antibodies were negative. Imaging confirmed the presence of fluid mainly in the suprapatellar bursa. Synovial fluid analysis revealed an inflammatory effusion, while other etiologies of inflammatory arthritis were excluded. INTERVENTIONS: Arthritis improved with an intra-articular injection of 8 mg dexamethasone. Twelve days later the arthritis relapsed in both knees, and although it was resistant to nonsteroidal anti-inflammatory treatment, it improved with systemic steroids. Tapering of methylprednisolone dose was feasible with the coadministration of leflunomide and subsequently hydroxychloroquine. OUTCOMES: Arthritis resolved and the patient is free of complications and disease activity 20 months after the initiation of the second line systemic treatment. CONCLUSIONS: We present an unusual case of IA associated with pembrolizumab treatment. The originality of the current report is based on the late occurrence, the monoarticular initial distribution, and uncommon location of IA at the knee.


Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Artritis Reumatoide/diagnóstico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Artritis Reumatoide/inducido químicamente , Diagnóstico Diferencial , Femenino , Humanos , Articulación de la Rodilla , Persona de Mediana Edad , Líquido Sinovial
5.
Dermatol Online J ; 26(1)2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32155032

RESUMEN

The combination of dabrafenib and trametinib is an important immunotherapy option for patients with BRAF V600 mutation-positive melanoma. This regimen has been reported to cause cutaneous eruptions. However, hair dysmorphology is not a reported side effect to these or any other medications to date. Herein, we highlight a case of pili multigemini formation in a patient with stage IV melanoma receiving treatment with dabrafenib and trametinib and the corresponding clinical findings.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedades del Cabello/inducido químicamente , Folículo Piloso/anomalías , Imidazoles/efectos adversos , Oximas/efectos adversos , Trastornos de la Pigmentación/inducido químicamente , Piridonas/efectos adversos , Pirimidinonas/efectos adversos , Cabello , Humanos , Imidazoles/uso terapéutico , Masculino , Melanoma/tratamiento farmacológico , Melanoma/secundario , Persona de Mediana Edad , Oximas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico
6.
Pediatrics ; 145(3)2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32051218

RESUMEN

Since the discovery of propranolol in the treatment of infantile hemangioma (IH), there has been emergent investigation of ß-adrenergic receptor (ß-AR) signaling in IH and the mechanisms of action for which ß-AR blockers regulate hemangioma cell proliferation. However, ß-AR agonists and antagonists are known to act antithetically via the same intracellular ß-AR-driven proangiogenic pathways. We present the case of a patient with involuted IH treated with propranolol that showed a full and rapid regrowth during the intravenous administration of salbutamol, a selective ß2-adrenergic agonist, for an episode of severe obstructive bronchitis. This observation brings forward the clinical implication of ß-signaling effects in IH and raises awareness of the potential proliferative response of IH to ß-AR agonists such as salbutamol.


Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Albuterol/efectos adversos , Hemangioma/patología , Recurrencia Local de Neoplasia/inducido químicamente , Neoplasias Cutáneas/patología , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Albuterol/administración & dosificación , Bronquitis/tratamiento farmacológico , Preescolar , Femenino , Hemangioma/tratamiento farmacológico , Humanos , Infusiones Intravenosas , Propranolol/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Vasodilatadores/uso terapéutico
7.
Cancer Immunol Immunother ; 69(5): 717-730, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32036449

RESUMEN

Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naïve metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease ≤ 6 months, N = 6). During therapy, the PB natural killer T (NKT) cell frequency, expression of CD25 and CD45RO on cytotoxic natural killer (NK) cells, and serum CXC chemokine levels were significantly increased in responders. Furthermore, higher age together with age-associated characteristics from PB, lower frequency of PB-naïve CD8+ T cells, and elevated levels of serum MCP-4 and OPG were discovered as baseline predictors of treatment response. We therefore propose that in addition to T cells, anti-PD1 treatment is associated with NK- and NKT-cell population dynamics, and that the age-associated characteristics from PB together with older age may contribute to prolonged PFS in anti-PD1-treated melanoma patients.


Asunto(s)
Envejecimiento/inmunología , Antineoplásicos Inmunológicos/farmacología , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Biopsia , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Resistencia a Antineoplásicos/inmunología , Femenino , Estudios de Seguimiento , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/inmunología , Nivolumab/farmacología , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Supervivencia sin Progresión , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología
9.
Adv Exp Med Biol ; 1226: 123-142, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030681

RESUMEN

Tumour microenvironment is a complex system comprising cells and molecules that will provide the necessary conditions for tumour development and progression. Cells residing in the tumour microenvironment gain specific phenotypes and specific functions that are pro-tumorigenic. Tumour progression is in fact a combination between tumour cell characteristics and its interplay with tumour microenvironment. This dynamic network will allow tumour cells to grow, migrate and invade tissues. In the present chapter, we are highlighting some traits that characterise tumour microenvironment in basal cell carcinoma, squamous cell carcinoma and cutaneous melanoma. In skin cancers, there are some common tumour microenvironment characteristics such as the presence of tumour-associated macrophages and regulatory T lymphocytes that are non-tumour cells promoting tumorigenesis. There are also skin cancer type differences in terms of tumour microenvironment characteristics. Thus, markers such as macrophage migration inhibitory factor in melanoma or the extraordinary diverse genetic make-up in the cancer-associated fibroblasts associated to squamous cell carcinoma are just a few of specific traits in skin cancer types. New technological advances for evaluation of tumour environment are presented. Thus, non-invasive skin imaging techniques such as reflectance confocal microscopy can evaluate skin tumour inflammatory infiltrates for density and cellular populations. Analysing tumour micromedium in depth may offer new insights into cancer therapy and identify new therapy targets.


Asunto(s)
Carcinogénesis , Neoplasias Cutáneas/patología , Microambiente Tumoral , Carcinogénesis/efectos de los fármacos , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos
10.
HNO ; 68(2): 100-105, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32006045

RESUMEN

This manuscript describes the functional properties of the exosomes released from melanoma cells. It details the characteristics of the tumor antigen chondroitin sulfate proteoglycan 4 (CSPG4), which is used as a marker to separate exosomes released by melanoma cells from exosomes released by nonmalignant cells. The results are discussed in view of the potential role of melanoma cell-derived exosomes in the escape of malignant cells from the host's immune system.


Asunto(s)
Proteoglicanos Tipo Condroitín Sulfato , Exosomas , Melanoma , Proteínas de la Membrana , Neoplasias Cutáneas , Antígenos , Biomarcadores/análisis , Líquidos Corporales , Proteoglicanos Tipo Condroitín Sulfato/análisis , Humanos , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Proteínas de la Membrana/análisis , Proteoglicanos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología
11.
Nat Commun ; 11(1): 437, 2020 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-31974367

RESUMEN

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Melanoma/tratamiento farmacológico , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos/patología , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones Endogámicos BALB C , Persona de Mediana Edad , Terapia Molecular Dirigida , Nivolumab/uso terapéutico , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Linfocitos T Reguladores/patología , Escape del Tumor/efectos de los fármacos , Escape del Tumor/fisiología
12.
PLoS One ; 15(1): e0227187, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31917795

RESUMEN

Receptor tyrosine kinase AXL is a one-pass transmembrane protein upregulated in cancers and associated with lower survival and therapy resistance. AXL can be cleaved by the A Disintegrin and Metalloproteinases (ADAM)10 and ADAM17, yielding a soluble version of the protein. Elevated soluble AXL (sAXL) has been reported to be associated with disease progression in hepatocellular carcinoma, renal cancer, neurofibromatosis type 1 and inflammatory diseases. In the present work, we analyzed sAXL levels in blood from melanoma patients and showed that sAXL increases with disease progression. Additionally, increased sAXL levels were found correlated with shorter two-year survival in stage IV patients treated with ipilimumab. Furthermore, we showed that sAXL levels were related to the percentage of cells expressing AXL in resected melanoma lymph node metastases. This finding was verified in vitro, where sAXL levels in the cell media corresponded to AXL expression in the cells. AXL inhibition using the small-molecular inhibitor BGB324 reduced sAXL levels, while the cellular expression was elevated through increased protein stability. Our findings signify that quantification of sAXL blood levels is a simple and easily assessable method to determine cellular AXL levels and should be further evaluated for its use as a biomarker of disease progression and treatment response.


Asunto(s)
Progresión de la Enfermedad , Melanoma/sangre , Melanoma/mortalidad , Proteínas Proto-Oncogénicas/sangre , Proteínas Tirosina Quinasas Receptoras/sangre , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Benzocicloheptenos/farmacología , Biomarcadores de Tumor/sangre , Línea Celular Tumoral , Femenino , Humanos , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Masculino , Melanoma/tratamiento farmacológico , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/química , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Solubilidad , Tasa de Supervivencia , Triazoles/farmacología
14.
Proc Natl Acad Sci U S A ; 117(2): 1119-1128, 2020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31888983

RESUMEN

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.


Asunto(s)
Inmunoterapia/métodos , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/uso terapéutico , Inyecciones Intralesiones , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Linfocitos B , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Linfocitos T CD8-positivos/inmunología , Humanos , Inmunidad Celular , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana , Interleucina-10 , Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Proteínas Represoras/genética , Estaciones del Año , Piel , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Escualeno/administración & dosificación , Microambiente Tumoral/efectos de los fármacos , Vacunación
15.
AAPS PharmSciTech ; 21(2): 51, 2020 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900659

RESUMEN

Vismodegib (VMD) is a hedgehog inhibitor which indicated for basal cell skin cancer (BCC). This work focuses on investigating the influence of isopropyl alcohol additive for topical delivering and targeting of VMD-loaded binary ethosomes for BCC treatment. Different binary ethosome formulae were prepared based on Box-Behnken design using different concentrations of phospholipid (A), cholesterol (B) and isopropyl alcohol/total alcohol ratio (C). The prepared formulae were characterized for %entrapment efficiency (R1), vesicle size (R2), %release (R3) and steady-state flux (R4). Increasing A, B and C resulted in significant increase of R1 and R2 and significant decrease of R3 and R4. The optimization was achieved and the optimum formula was selected to investigate its anti-tumour efficacy in vivo. The optimum formula showed a localized VMD and consequently a significant anti-tumour activity compared with oral VMD. Briefly, VMD-loaded binary ethosome gel could be an effective treatment of BCC with lower side effects. Graphical abstract.


Asunto(s)
Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Piridinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Humanos , Ratas , Resultado del Tratamiento
16.
Photochem Photobiol Sci ; 19(2): 171-179, 2020 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-31942903

RESUMEN

Nicotinamide (NAM), an amide form of vitamin B3, replenishes cellular energy after ultraviolet radiation (UVR) exposure, thereby enhancing DNA repair and reducing UVR's immunosuppressive effects. NAM reduces actinic keratoses and new keratinocyte cancers in high risk individuals, but its effects on melanoma are unknown. Melanomas arising on NAM or placebo within the ONTRAC skin cancer chemoprevention trial (Oral Nicotinamide To Reduce Actinic Cancer) were examined by immunohistochemistry. The effects of NAM (50 µM, 5 mM and 20 mM) on the viability, proliferation and invasiveness of four human melanoma cell lines and on the viability and proliferation of two human melanocyte lines, with and without UV irradiation were also investigated. 50 µM NAM did not affect viability, proliferation or invasion of melanoma or melanocyte cell lines, whereas concentrations too high to be achievable in vivo reduced viability and proliferation. Nicotinamide did not enhance melanoma viability, proliferation or invasiveness in vitro, providing additional confidence in its safety for use in clinical trials in high risk patients. Peritumoral and tumour infiltrating CD4+ and CD8+ lymphocytes were significantly increased in melanomas arising on NAM compared to those arising on placebo. Given the chemopreventive activity of nicotinamide against keratinocyte cancers, its DNA repair enhancing effects in melanocytes and now its potential enhancement of tumour-infiltrating lymphocytes and lack of adverse effects on melanoma cell growth and proliferation, clinical trials of nicotinamide for melanoma chemoprevention are now indicated.


Asunto(s)
Melanoma/patología , Niacinamida/farmacología , Neoplasias Cutáneas/patología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Melanoma/tratamiento farmacológico , Melanoma/prevención & control , Niacinamida/química , Niacinamida/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Rayos Ultravioleta
17.
J Clin Pathol ; 73(2): 116-119, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31506288

RESUMEN

Beyond targeted therapy for patients with BRAF-mutated melanomas and immunotherapy in patients lacking BRAF mutations, anti-MEK therapy has been proposed in patients with advanced melanomas harbouring BRAF fusions. BRAF fusions diagnosis in patients with advanced melanomas is the subject of the present study. Using BRAF fluorescent in situ hybridisation (FISH), we searched for BRAF fusions in 74 samples of 66 patients with advanced BRAF/NRAS/KIT wild-type melanomas. We identified 2/66 (3%) patients with BRAF fusions in a brain metastasis of one patient and in a lymph node metastasis and in a cutaneous metastasis for the second patient with 90%-95% of tumour nuclei containing isolated 3'-BRAF FISH signals. As a result, we conclude that BRAF FISH in patients with advanced BRAF/NRAS/KIT wild-type melanomas is a valuable and easy-to-perform test to diagnose BRAF fusions and to identify patients who could benefit of anti-MEK targeted therapy.


Asunto(s)
Biomarcadores de Tumor/genética , GTP Fosfohidrolasas/genética , Fusión Génica , Hibridación Fluorescente in Situ , Melanoma/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-kit/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Femenino , Humanos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/enzimología , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Terapia Molecular Dirigida , Selección de Paciente , Medicina de Precisión , Valor Predictivo de las Pruebas , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/enzimología
18.
Int J Cancer ; 146(6): 1652-1666, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31180579

RESUMEN

Viruses can inhibit host autophagy through multiple mechanisms, and evasion of autophagy plays an important role in immune suppression and viral oncogenesis. Merkel cell polyomavirus (MCPyV) T-antigens are expressed and involved in the pathogenesis of a large proportion of Merkel cell carcinoma (MCC). Yet, how MCPyV induces tumorigenesis is not fully understood. Herein, we show that MCPyV T-antigens induce miR-375, miR-30a-3p and miR-30a-5p expressions, which target multiple key genes involved in autophagy, including ATG7, SQSTM1 (p62) and BECN1. In MCC tumors, low expression of ATG7 and p62 are associated with MCPyV-positive tumors. Ectopic expression of MCPyV small T-antigen and truncated large T-antigen (LT), but not the wild-type LT, resulted in autophagy suppression, suggesting the importance of autophagy evasion in MCPyV-mediated tumorigenesis. Torin-1 treatment induced cell death, which was attenuated by autophagy inhibitor, but not pan-caspase inhibitor, suggesting a potential role of autophagy in promoting cell death in MCC. Conceptually, our study shows that MCPyV oncoproteins suppress autophagy to protect cancer cells from cell death, which contribute to a better understanding of MCPyV-mediated tumorigenesis and potential MCC treatment.


Asunto(s)
Carcinoma de Células de Merkel/virología , Poliomavirus de Células de Merkel/metabolismo , MicroARNs/biosíntesis , Neoplasias Cutáneas/virología , Antígenos Virales de Tumores/metabolismo , Autofagia/efectos de los fármacos , Autofagia/genética , Proteína 7 Relacionada con la Autofagia/biosíntesis , Proteína 7 Relacionada con la Autofagia/genética , Beclina-1/biosíntesis , Beclina-1/genética , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/patología , Línea Celular Tumoral , Humanos , Macrólidos/farmacología , MicroARNs/genética , MicroARNs/metabolismo , Naftiridinas/farmacología , Infecciones por Polyomavirus/genética , Infecciones por Polyomavirus/metabolismo , Infecciones por Polyomavirus/patología , Infecciones por Polyomavirus/virología , Procesamiento Postranscripcional del ARN , Proteína Sequestosoma-1/biosíntesis , Proteína Sequestosoma-1/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Infecciones Tumorales por Virus/genética , Infecciones Tumorales por Virus/metabolismo , Infecciones Tumorales por Virus/patología , Infecciones Tumorales por Virus/virología
20.
Int J Cancer ; 146(5): 1409-1420, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31702822

RESUMEN

Therapeutic success of targeted therapy with BRAF inhibitors (BRAFi) for melanoma is limited by resistance development. Observations from preclinical mouse models and recent insights into the immunological effects caused by BRAFi give promise for future development of combination therapy for human melanoma. In our study, we used the transplantable D4M melanoma mouse model with the BRAFV600E mutation and concomitant PTEN loss in order to characterize alterations in tumor-infiltrating effector immune cells when tumors become resistant to BRAFi. We found that BRAFi-sensitive tumors displayed a pronounced inflammatory milieu characterized by high levels of cytokines and chemokines accompanied by an infiltration of T and NK cells. The tumor-infiltrating effector cells were activated and produced high levels of IFN-γ, TNF-α and granzyme B. When tumors became resistant and progressively grew, they reverted to a low immunogenic state similar to untreated tumors as reflected by low mRNA levels of proinflammatory cytokines and chemokines and fewer tumor-infiltrating T and NK cells. Moreover, these T and NK cells were functionally impaired in comparison to their counterparts in BRAFi-sensitive tumors. Their effector cell function could be restored by additional peritumoral treatment with the TLR7 agonist imiquimod, a clinically approved agent for nonmelanoma skin cancer. Indeed, resistance to BRAFi therapy was delayed and accompanied by high numbers of activated T and NK cells in tumors. Thus, combining BRAFi with an immune stimulating agent such as a TLR ligand could be a promising alternative approach for the treatment of melanoma.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral/trasplante , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Femenino , Humanos , Imiquimod/farmacología , Imiquimod/uso terapéutico , Indoles/farmacología , Indoles/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/metabolismo , Ratones , Mutación , Células T Asesinas Naturales , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 7/metabolismo
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