Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 12.342
Filtrar
1.
Anticancer Res ; 40(9): 5245-5254, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878813

RESUMO

BACKGROUND/AIM: To determine whether BMI and sarcopenia were related to treatment-limiting toxicity or efficacy of pembrolizumab treatment in melanoma patients. PATIENTS AND METHODS: Medical records for melanoma patients undergoing pembrolizumab treatment at Duke University from January 2014 to September 2018 were reviewed. Pre-treatment measurements such as BMI were collected. Pre-treatment CT imaging was used to determine psoas muscle index (PMI). Patients in the lowest sex-specific tertile of PMI were sarcopenic. Logistic regression measured associations with treatment toxicity and response. Kaplan-Meier analysis assessed progression-free survival (PFS) and overall survival (OS). RESULTS: Among 156 patients, the overall objective response rate was 46.2% and 29 patients (18.6%) experienced treatment-limiting toxicity. Sarcopenia was not significantly associated with toxicity, response, or survival. However, obese patients (BMI >30) experienced higher rates of toxicity (p=0.0007). CONCLUSION: Sarcopenia did not appear to predict clinically relevant outcomes. Obesity, however, represents a readily available predictor of pembrolizumab toxicity.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Índice de Massa Corporal , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Melanoma/complicações , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/etiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prognóstico , Sarcopenia/complicações , Tomografia Computadorizada por Raios X , Adulto Jovem
2.
N Engl J Med ; 383(12): 1139-1148, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32877599

RESUMO

BACKGROUND: In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed. METHODS: We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached. RESULTS: The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period. CONCLUSIONS: In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/uso terapêutico , Melanoma/tratamento farmacológico , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/genética , Análise de Sobrevida
3.
Nat Commun ; 11(1): 3946, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770055

RESUMO

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Melanoma/tratamento farmacológico , Proteínas do Tecido Nervoso/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , RNA-Seq , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/metabolismo , Evasão Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Mutat Res ; 785: 108321, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32800272

RESUMO

BRAF is a member of the RAF family of serine/threonine-specific protein kinases. Oncogenic BRAF, in particular, BRAF V600E, can disturb the normal protein folding machinery in the endoplasmic reticulum (ER) leading to accumulation of unfolded/misfolded proteins in the ER lumen, a condition known as endoplasmic reticulum (ER) stress. To alleviate such conditions, ER-stressed cells have developed a highly robust and adaptable signaling network known as unfolded protein response (UPR). UPR is ordinarily a cytoprotective response and usually operates through the induction of autophagy, an intracellular lysosomal degradation pathway that directs damaged proteins, protein aggregates, and damaged organelles for bulk degradation and recycling. Both ER stress and autophagy are involved in the progression and chemoresistance of melanoma. Melanoma, which arises as a result of malignant transformation of melanocytes, exhibits exceptionally high therapeutic resistance. Many mechanisms of therapeutic resistance have been identified in individual melanoma patients and in preclinical BRAF-driven melanoma models. Recently, it has been recognized that oncogenic BRAF interacts with GRP78 and removes its inhibitory influence on the three fundamental ER stress sensors of UPR, PERK, IRE1α, and ATF6. Dissociation of GRP78 from these ER stress sensors prompts UPR that subsequently activates cytoprotective autophagy. Thus, pharmacological inhibition of BRAF-induced ER stress-mediated autophagy can potentially resensitize BRAF mutant melanoma tumors to apoptosis. However, the underlying molecular mechanism of how oncogenic BRAF elevates the basal level of ER stress-mediated autophagy in melanoma tumors is not well characterized. A better understanding of the crosstalk between oncogenic BRAF, ER stress and autophagy may provide a rationale for improving existing cancer therapies and identify novel targets for therapeutic intervention of melanoma.


Assuntos
Autofagia , Resistencia a Medicamentos Antineoplásicos , Estresse do Retículo Endoplasmático , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Resposta a Proteínas não Dobradas , Apoptose , Humanos , Melanoma/tratamento farmacológico , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico
6.
Yonsei Med J ; 61(7): 562-571, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32608199

RESUMO

Melanoma, originating from epidermal melanocytes, is a heterogeneous disease that has the highest mortality rate among all types of skin cancers. Numerous studies have revealed the cause of this cancer as related to various somatic driver mutations, including alterations in KIT-a proto-oncogene encoding for a transmembrane receptor tyrosine kinase. Although accounting for only 3% of all melanomas, mutations in c-KIT are mostly derived from acral, mucosal, and chronically sun-damaged melanomas. As an important factor for cell differentiation, proliferation, and survival, inhibition of c-KIT has been exploited for clinical trials in advanced melanoma. Here, apart from the molecular background of c-KIT and its cellular functions, we will review the wide distribution of alterations in KIT with a catalogue of more than 40 mutations reported in various articles and case studies. Additionally, we will summarize the association of KIT mutations with clinicopathologic features (age, sex, melanoma subtypes, anatomic location, etc.), and the differences of mutation rate among subgroups. Finally, several therapeutic trials of c-KIT inhibitors, including imatinib, dasatinib, nilotinib, and sunitinib, will be analyzed for their success rates and limitations in advanced melanoma treatment. These not only emphasize c-KIT as an attractive target for personalized melanoma therapy but also propose the requirement for additional investigational studies to develop novel therapeutic trials co-targeting c-KIT and other cytokines such as members of signaling pathways and immune systems.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Feminino , Humanos , Masculino , Melanoma/genética , Membrana Mucosa/metabolismo , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Proteína Tirosina Quinases/genética , Neoplasias Cutâneas/genética
7.
Medicine (Baltimore) ; 99(29): e21329, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702928

RESUMO

In BRAF wild type advanced melanoma, immune checkpoint blockers such as anti-PD1 (anti-programmed cell death 1) are usually continued beyond progression for a hypothetical rare further response. Chemotherapy as a second-line option is considered ineffective by many practitioners based on historical data. Continuing anti-PD1 beyond progression has a high health-economic impact and is not recommended by the FDA. This study aimed to describe the efficacy and survival of advanced melanoma patients who received second-line (or more) chemotherapy after immunotherapy failure.This was a retrospective single center study conducted in a French University Hospital during an 11-month period. All advanced melanoma patients treated with chemotherapy after immunotherapy failure were included.Eighteen patients were analyzed. Therapeutic response to chemotherapy was evaluable in 16 patients: partial response was achieved in 3/16 (19%), stable disease in 1/16 (6%) and progressive disease in 12/16 (75%). Median overall survival from chemotherapy start was 12 months. Median progression-free survival was 5.4 months. The 6-month overall survival rate was 81% and the 6-month progression-free survival rate was 40%.Although the disease control rate with chemotherapy was low (25%), survival data in our study are far superior to those previously published. This could be linked to a high proportion of patients treated with anti-PD1 just prior to chemotherapy, which may suggest a potential synergy between immunotherapy and chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Quimioterapia Adjuvante , Terapia Combinada , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
8.
Nature ; 585(7823): 107-112, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728218

RESUMO

Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours1,2. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4+ and CD8+ T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.


Assuntos
Antineoplásicos/uso terapêutico , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Melanoma/imunologia , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Neoplásico/genética , Linfócitos T/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos/farmacologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Terapia Combinada , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Estadiamento de Neoplasias , Linfócitos T/citologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Vacinação
9.
Lancet ; 395(10240): 1835-1844, 2020 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-32534646

RESUMO

BACKGROUND: IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma. METHODS: IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients. FINDINGS: Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events. INTERPRETATION: The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma. FUNDING: F Hoffmann-La Roche and Genentech.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azetidinas/uso terapêutico , Melanoma/tratamento farmacológico , Piperidinas/uso terapêutico , Vemurafenib/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azetidinas/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Piperidinas/efeitos adversos , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/efeitos adversos
10.
Autoimmun Rev ; 19(8): 102587, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32553612

RESUMO

Therapy for advanced melanoma has deeply changed in the last decade with the introduction of checkpoint and BRAF/MEK inhibitors. Granulomatous reactions have been reported related to these drugs. We performed a systematic review of all the cases described in the medical literature by the search (("Melanoma"[Mesh]) AND ("Sarcoidosis"[Mesh] OR "Granuloma"[Mesh])). Ninety-one patients under immunotherapy were included in the analyses. The time from the initiation of the immunotherapy until the onset of sarcoidosis or sarcoid-like reaction (SLR) was 7.1 months (SD 9). Peripheral lymph nodes as the mode of onset were seen more frequently in patients under CTLA-4 inhibitors (p = .016) whereas in patients under BRAF/MEK inhibitors used to be in the form of specific skin lesions (p = .006). Chest X-ray stage I-II was the rule in the CTLA-4 and PD-1 groups. On the contrary, stage 0 accounted for 80% of the patients in the BRAF/MEK group examined for pulmonary involvement. Specific skin involvement was the most common manifestation apart from pulmonary involvement. It was more frequent in patients under BRAF/MEK inhibitors and especially in the form of papules. Splenic involvement was found also more frequently in patients under CTLA-4 inhibitors. Specific treatment for sarcoidosis/SLR was prescribed in 50 patients (58.8%), without differences among groups. Almost all patients presented a good prognosis independently of the decision made regarding their previous immunotherapy. CONCLUSION: Physicians should bear in mind the possibility of sarcoidosis/SLR after the initiation of checkpoint or BRAF/MEK inhibitors in patients diagnosed with advanced melanoma, especially in the form of skin involvement and mediastinal and peripheral lymph nodes. It is important to achieve an accurate diagnosis to rule out the possibility of cancer involvement. What to do with these drugs is yet to be clarified. It seems reasonable to prioritize cancer treatment so it is not mandatory to stop these drugs.


Assuntos
Antineoplásicos , Imunoterapia , Melanoma , Sarcoidose , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Humanos , Imunoterapia/efeitos adversos , MAP Quinase Quinase 1/antagonistas & inibidores , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sarcoidose/induzido quimicamente
11.
Toxicol Appl Pharmacol ; 401: 115110, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32533954

RESUMO

Melanoma is characterized by high malignancy and early onset of metastasis. Epithelial-to-mesenchymal transition (EMT) is an early event during tumor metastasis. Tumor cells that develop EMT can escape apoptosis, but they are vulnerable to ferroptosis inducers. Gambogenic acid (GNA), a xanthone found in Gamboge, has cytotoxic effects in highly invasive melanoma cells. This study investigated the anti-melanoma effect and mechanism of action of GNA in TGF-ß1-induced EMT melanoma cells. We found that GNA significantly inhibited the invasion, migration and EMT in melanoma cells, and these cells exhibited small mitochondrial wrinkling (an important feature of ferroptosis). An iron chelator, but not an apoptosis inhibitor or a necrosis inhibitor, abolished the inhibitory effects of GNA on proliferation, invasion and migration of TGF-ß1-stimulated melanoma cells. GNA upregulated the expression of p53, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in the model cells, contributing to the mechanisms underlying GNA-induced ferroptosis. Collectively, our findings suggest that GNA induces ferroptosis in TGF-ß1-stimulated melanoma cells via the p53/SLC7A11/GPX4 signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Xantenos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transição Epitelial-Mesenquimal/fisiologia , Ferroptose/fisiologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Xantenos/uso terapêutico
12.
PLoS One ; 15(6): e0234707, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555626

RESUMO

Despite significant development of melanoma therapies, death rates remain high. MicroRNAs, controlling posttranscriptionally gene expression, play role in development of resistance to BRAF inhibitors. The aim of the study was to assess the role of miR-410-3p in response to vemurafenib-BRAF inhibitor. FFPE tissue samples of 12 primary nodular melanomas were analyzed. With the use of Laser Capture Microdissection, parts of tumor, transient tissue, and adjacent healthy tissue were separated. In vitro experiments were conducted on human melanoma cell lines A375, G361, and SK-MEL1. IC50s of vemurafenib were determined using MTT method. Cells were transfected with miR-410-3p mimic, anti-miR-410-3p and their non-targeting controls. ER stress was induced by thapsigargin. Expression of isolated RNA was determined using qRT-PCR. We have found miR-410-3p is downregulated in melanoma tissues. Its expression is induced by vemurafenib in melanoma cells. Upregulation of miR-410-3p level increased melanoma cells resistance to vemurafenib, while its inhibition led to the decrease of resistance. Induction of ER stress increased the level of miR-410-3p. miR-410-3p upregulated the expression of AXL in vitro and correlated with markers of invasive phenotype in starBase. The study shows a novel mechanism of melanoma resistance. miR-410-3p is induced by vemurafenib in melanoma cells via ER stress. It drives switching to the invasive phenotype that leads to the response and resistance to BRAF inhibition.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Melanoma/genética , MicroRNAs/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Vemurafenib/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Vemurafenib/uso terapêutico
13.
Nat Commun ; 11(1): 2858, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504051

RESUMO

Metastatic melanoma is challenging to manage. Although targeted- and immune therapies have extended survival, most patients experience therapy resistance. The adaptability of melanoma cells in nutrient- and therapeutically-challenged environments distinguishes melanoma as an ideal model for investigating therapy resistance. In this review, we discuss the current available repertoire of melanoma models including two- and three-dimensional tissue cultures, organoids, genetically engineered mice and patient-derived xenograft. In particular, we highlight how each system recapitulates different features of melanoma adaptability and can be used to better understand melanoma development, progression and therapy resistance.


Assuntos
Antinematódeos/farmacologia , Modelos Animais de Doenças , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antinematódeos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Camundongos , Camundongos Transgênicos , Organoides , Pele/citologia , Pele/imunologia , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Esferoides Celulares
14.
Drug Discov Ther ; 14(3): 117-121, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32595179

RESUMO

The advent of immune checkpoint inhibitors such as anti-PD-1 antibodies had a striking impact on the treatment for advanced malignant melanoma. However, less than half of the patients benefited from those antibodies, and biomarkers that could sensitively differentiate responders from non-responders are urgently needed. Herein, we explored such biomarkers by retrospectively analyzing clinical data from patients with advanced malignant melanoma treated with nivolumab and pembrolizumab. We found that anti-PD-1 antibody was especially effective for those with metastasis only to soft tissues. Although no significant difference was found in the baseline value of relative neutrophil count (RNC), relative lymphocyte count (RLC), neutrophil to lymphocyte ratio (NLR), and relative eosinophil count (REC) between responders and non-responders, responders after anti-PD-1 therapy revealed the increase of lymphocytes and eosinophils and the decrease of neutrophils within the first 6 weeks of the treatment. We also calculated the change of RNC and RLC 3 weeks and 6 weeks after the initiation of the therapy and designated as NΔ3-LΔ3 and NΔ6-LΔ6 respectively. NΔ3-LΔ3 was significantly decreased in responders, which suggest that the neutrophil decrease and lymphocyte increase after as early as 3 weeks of anti-PD-1 therapy might be a useful clinical indicator. In addition, the difference of NΔ6-LΔ6 between responders and non-responders was even more robust. These data suggest that change of RNC, RLC, and REC together with the combination of NΔ3-LΔ3 and NΔ6-LΔ6 might be a useful tool for early and sensitive biomarkers for anti-PD-1 therapy.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptor de Morte Celular Programada 1/sangue , Estudos Retrospectivos , Neoplasias Cutâneas/sangue , Resultado do Tratamento
15.
Medicine (Baltimore) ; 99(25): e20705, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569203

RESUMO

INTRODUCTION: Resistance to targeted and immune checkpoint blockade treatment remains a major problem in patients with advanced metastatic melanoma. To overcome this problem, there needs to be a decrease in burden of disease as well as re-establishing of immune sensitivity. The aim of this early phase 2 clinical trial is to investigate a novel way of sequencing and combining decitabine and carboplatin to decrease methylation and increase DNA repair resulting in a decrease in the disease burden and to re-establish sensitivity to the immune response. METHODS AND ANALYSIS: This single-site early phase 2 clinical trial will be conducted in 30 patients with metastatic melanoma that are resistant to all approved therapies. Patients will receive 2 × 4-week cycles of decitabine 7 mg/m IVI/day for 5 days (D1-D5) followed by Carboplatin AUC 5 IVI on D8; Week 3 and Week 4 no treatment. The primary objective is to determine DNA methylation and DNA repair levels before, and immediately after treatment; quantify immune-response markers (PDL-1, PD-1, CD4/CD8, and CD68) in blood, tumor and microenvironment before treatment and after 2 cycles. The secondary outcome objective is to quantify response rate (RR) to administration of 2 cycles of decitabine and carboplatin cycle using response evaluation criteria in solid tumors (RECIST 1.1) criteria. This data will be used to calculate sample size and determine statistical analysis plan for larger Phase 2 study. ETHICS AND DISSEMINATION: Protocol version 1.1 was reviewed and approved by the Hunter New England Health Human Research Ethics Committee (Reference No: 15/12/16/3.08, NSW HREC Reference No: HREC/15/HNE/505) and site-specific approval from the Calvary Mater Hospital Newcastle, NSW, Australia (NSW SSA Reference No: SSA/16/HNE/224). Primary and secondary outcomes and safety data will be disseminated through publications. TRIAL REGISTRATION DETAILS: Australian New Zealand Clinical Trial Registry ACTRN12616000440426.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Decitabina/uso terapêutico , Melanoma/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Humanos , Melanoma/patologia , Projetos Piloto
17.
Crit Rev Oncol Hematol ; 153: 102995, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32569852

RESUMO

Several evidences indicate that melanoma, one of the deadliest types of cancer, presents the ability to transiently shift its phenotype under treatment or microenvironmental pressure to an invasive and treatment-resistant phenotype, which is characterized by cells with slow division cycle (also called slow-cycling cells) and high-OXPHOS metabolism. Many cellular marks have been proposed to track this phenotype, such as the expression levels of the master regulator of melanocyte differentiation (MITF) and the epigenetic factor JARID1B. It seems that the slow-cycling phenotype does not necessarily present a single gene expression signature. However, many lines of evidence lead to a common metabolic rewiring process in resistant cells that activates mitochondrial metabolism and changes the mitochondrial network morphology. Here, we propose that mitochondria-targeted drugs could increase not only the efficiency of target therapy, bypassing the dynamics between fast-cycling and slow-cycling, but also the sensitivity to immunotherapy by modulation of the melanoma microenvironment.


Assuntos
Melanoma/tratamento farmacológico , Ciclo Celular , Linhagem Celular Tumoral , Humanos , Imunoterapia , Mitocôndrias/genética , Fenótipo , Microambiente Tumoral
18.
J Cancer Res Ther ; 16(2): 387-392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474528

RESUMO

Primary anorectal malignant melanoma (ARMM) is an extremely rare but aggressive tumor. We assessed the efficacy and safety of transcatheter arterial infusion (TAI) with anti-PD-1 antibody pembrolizumab at a dosage of 100 mg with 0.9% NaCl at a volume of 100 mL administered over a 30-min period every 3 weeks, combined with temozolomide or albumin-bound paclitaxel (nab-paclitaxel) in four patients with ARMM. Temozolomide was administered orally once per day at a dosage of 200 mg/m2/d for five consecutive days about every 4 weeks. Nab-paclitaxel was administered at a dosage of 200mg/m2/d once about every 3 weeks. Among four patients with a median follow-up of 8.9 months, two cases showed Murine Double Minute 2 (MDM2) amplification. Case 1 with Stage II ARMM showed pathological complete response after four cycles of TAI with pembrolizumab combined with nab-paclitaxel. Case 4 was at Stage II and showed stable disease consistently throughout the treatment. Case 2 was at stage II and Case 3 was at stage III, and they showed partial response after four or three cycles, respectively, of TAI with pembrolizumab combined with temozolomide. No Grades 3-4 adverse reactions were observed. Therefore, a combination of TAI with pembrolizumab and temozolomide or with nab-paclitaxel appears to be a promising option for treating ARMM. However, multicenter clinical trials are required to confirm the efficacy and safety of this procedure.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Infusões Intra-Arteriais/métodos , Melanoma/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Adulto , Albuminas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias do Ânus/patologia , Feminino , Humanos , Melanoma/patologia , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Segurança do Paciente , Neoplasias Retais/patologia , Temozolomida/administração & dosagem , Resultado do Tratamento
19.
J Cancer Res Clin Oncol ; 146(11): 3003-3012, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32564137

RESUMO

BACKGROUND: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) is a novel interventional procedure, which delivers high doses of melphalan directly to the liver in patients with liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. We have previously shown promising efficacy for patients with ocular melanoma (OM) and cholangiocarcinoma (CCA) within our single-center and multi-center experiences. The aim of this study was to analyze the safety and efficacy of CS-PHP after 141 treatments at Hannover Medical School, Germany. METHODS: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST1.1). Median Overall survival (mOS), median progression-free survival (mPFS), and median hepatic PFS (mhPFS) were analyzed using the Kaplan-Meier estimation. RESULTS: Overall, 60 patients were treated with CS-PHP in the salvage setting from October 2014 until January 2019 at Hannover Medical School with a total of 141 procedures. Half of the patients were patients with hepatic metastases of ocular melanoma (OM) (n = 30), 14 patients had CCA (23.3%), 6 patients had hepatocellular carcinoma (10%), and 10 patients were treated for other secondary liver malignancies (16.7%). In total, ORR and disease stabilization rate were 33.3% and 70.3% (n = 25), respectively. ORR was highest for patients with OM (42.3%), followed by patients with CCA (30.8%). Independent response-associated factors were normal levels of lactate dehydrogenase (odds ratio (OR) 13.7; p = 0.015) and diagnosis with OM (OR 9.3; p = 0.028). Overall, mOS was 9 months, mPFS was 4 months, and mhPFS was 5 months. Patients with OM had the longest mOS, mPFS, and mhPFS with 12, 6, and 6 months, respectively. Adverse events included most frequently significant, but transient, hematologic toxicities (80% of grade 3/4 thrombopenia), less frequently hepatic injury up to liver failure (3.3%) and cardiovascular events including two cases of ischemic insults (5%). CONCLUSION: Salvage treatment with CS-PHP is safe and effective particularly in patients OM and CCA. Careful attention should be paid to possible, serious hepatic, and cardiovascular complications.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Quimioterapia do Câncer por Perfusão Regional , Colangiocarcinoma/tratamento farmacológico , Melanoma/tratamento farmacológico , Melfalan/administração & dosagem , Neoplasias Uveais/tratamento farmacológico , Idoso , Neoplasias dos Ductos Biliares/patologia , Quimioterapia do Câncer por Perfusão Regional/instrumentação , Quimioterapia do Câncer por Perfusão Regional/métodos , Colangiocarcinoma/patologia , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Terapia de Salvação/instrumentação , Terapia de Salvação/métodos , Neoplasias Uveais/secundário
20.
Eur J Cancer ; 135: 147-149, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32585589
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA