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1.
PLoS One ; 15(9): e0238529, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966289

RESUMO

Amelanotic/hypomelanotic melanoma is a clinicopathologic subtype with absent or minimal melanin. This study assessed previously reported coding variants in albinism genes (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, LRMDA) and common intronic, regulatory variants of OCA2 in individuals with amelanotic/hypomelanotic melanoma, pigmented melanoma cases and controls. Exome sequencing was available for 28 individuals with amelanotic/hypomelanotic melanoma and 303 individuals with pigmented melanoma, which were compared to whole exome data from 1144 Australian controls. Microarray genotyping was available for a further 17 amelanotic/hypomelanotic melanoma, 86 pigmented melanoma, 147 melanoma cases (pigmentation unknown) and 652 unaffected controls. Rare deleterious variants in TYR/OCA1 were more common in amelanotic/hypomelanotic melanoma cases than pigmented melanoma cases (set mixed model association tests P = 0.0088). The OCA2 hypomorphic allele p.V443I was more common in melanoma cases (1.8%) than controls (1.0%, X2 P = 0.02), and more so in amelanotic/hypomelanotic melanoma (4.4%, X2 P = 0.007). No amelanotic/hypomelanotic melanoma cases carried an eye and skin darkening haplotype of OCA2 (including rs7174027), present in 7.1% of pigmented melanoma cases (P = 0.0005) and 9.4% controls. Variants in TYR and OCA2 may play a role in amelanotic/hypomelanotic melanoma susceptibility. We suggest that somatic loss of function at these loci could contribute to the loss of tumor pigmentation, consistent with this we found a higher rate of somatic mutation in TYR/OCA2 in amelanotic/hypomelanotic melanoma vs pigmented melanoma samples (28.6% vs 3.0%; P = 0.021) from The Cancer Genome Atlas Skin Cutaneous Melanoma collection.

2.
Theranostics ; 10(14): 6261-6277, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483452

RESUMO

Despite the recent advances in the treatment of cancers, acquired drug resistance remains a major challenge in cancer management. While earlier studies suggest Darwinian factors driving acquired drug resistance, recent studies point to a more dynamic process involving phenotypic plasticity and tumor heterogeneity in the evolution of acquired drug resistance. Chronic stress after drug treatment induces intrinsic cellular reprogramming and cancer stemness through a slow-cycling persister state, which subsequently drives cancer progression. Both epigenetic and metabolic mechanisms play an important role in this dynamic process. In this review, we discuss how epigenetic and metabolic reprogramming leads to stress-induced phenotypic plasticity and acquired drug resistance, and how the two reprogramming mechanisms crosstalk with each other.

5.
Epigenomics ; 11(7): 732-737, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31070054

RESUMO

Aim: To investigate the integrated epigenetic regulation of acquired drug resistance in cancer. Materials & methods: Our gene expression data of five induced drug-tolerant cell models, one resistant cell line and one publicly available drug-resistant dataset were integrated to identify common differentially expressed genes and pathways. ChIP-seq and DNA methylation by HM450K beadchip were used to study the epigenetic profile of differential expressed genes. Results & conclusion: Integrated transcriptomic analysis identified a common 'viral mimicry' related gene signature in induced drug-tolerant cells and the resistant state. Analysis of the epigenetic regulation revealed a common set of down-regulated genes, which are marked and regulated by a concomitant loss of H3K4me3, gain of H3K9me3 and increment of regional DNA methylation levels associated with tumor suppressor genes and apoptotic signaling.

6.
Sci Rep ; 9(1): 4096, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30858407

RESUMO

Melanoma is a leading cause of high mortality that frequently spreads to the brain and is associated with deterioration in quality and quantity of life. Treatment opportunities have been restricted until now and new therapy options are urgently required. Our focus was to reveal the potential heterogeneity of melanoma brain metastasis. We succeeded to establish a brain melanoma metastasis cell line, namely MUG-Mel1 and two resulting clones D5 and C8 by morphological variety, differences in lipidome, growth behavior, surface, and stem cell markers. Mutation analysis by next-generation sequencing, copy number profiling, and cytogenetics demonstrated the different genetic profile of MUG-Mel1 and clones. Tumorigenicity was unsuccessfully tested in various mouse systems and finally established in a zebra fish model. As innovative treatment option, with high potential to pass the blood-brain barrier a peptide isolated from lactoferricin was studied in potential toxicity. Brain metastases are a major clinical challenge, therefore the development of relevant in vitro and in vivo models derived from brain melanoma metastases provides valuable information about tumor biology and offers great potential to screen for new innovative therapies.

7.
Clin Epigenetics ; 11(1): 43, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850015

RESUMO

BACKGROUND: A multitude of recent studies has observed common epigenetic changes develop in tumour cells of multiple lineages following exposure to stresses such as hypoxia, chemotherapeutics, immunotherapy or targeted therapies. A significant increase in the transcriptionally repressive mark trimethylated H3K9 (H3K9me3) is becoming associated with treatment-resistant phenotypes suggesting upstream mechanisms may be a good target for therapy. We have reported that the increase in H3K9me3 is derived from the methyltransferases SETDB1 and SETDB2 following treatment in melanoma, lung, breast and colorectal cancer cell lines, as well as melanoma patient data. Other groups have observed a number of characteristics such as epigenetic remodelling, increased interferon signalling, cell cycle inhibition and apoptotic resistance that have also been reported by us suggesting these independent studies are investigating similar or identical phenomena. MAIN BODY: Firstly, this review introduces reports of therapy-induced reprogramming in cancer populations with highly similar slow-cycling phenotypes that suggest a role for both IFN signalling and epigenetic remodelling in the acquisition of drug tolerance. We then describe plausible connections between the type 1 IFN pathway, slow-cycling phenotypes and these epigenetic mechanisms before reviewing recent evidence on the roles of SETDB1 and SETDB2, alongside their product H3K9me3, in treatment-induced reprogramming and promotion of drug resistance. The potential mechanisms for the activation of SETDB1 and SETDB2 and how they might arise in treatment is also discussed mechanistically, with a focus on their putative induction by inflammatory signalling. Moreover, we theorise their timely role in attenuating inflammation after their activation in order to promote a more resilient phenotype through homeostatic coordination of H3K9me3. We also examine the relatively uncharacterized functions of SETDB2 with some comparison to the more well-known qualities of SETDB1. Finally, an emerging overall mechanism for the epigenetic maintenance of this transient phenotype is outlined by summarising the collective literature herein. CONCLUSION: A number of converging phenotypes outline a stress-responsive mechanism for SETDB1 and SETDB2 activation and subsequent increased survival, providing novel insights into epigenetic biology. A clearer understanding of how SETDB1/2-mediated transcriptional reprogramming can subvert treatment responses will be invaluable in improving length and efficacy of modern therapies.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Neoplasias/metabolismo , Animais , Reprogramação Celular , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interferon Tipo I/metabolismo , Neoplasias/tratamento farmacológico , Fenótipo , Transdução de Sinais
8.
Cancer Med ; 8(3): 1186-1196, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30793515

RESUMO

Most BRAF-mutant melanoma patients experience a fulminate relapse after several months of treatment with BRAF/MEK inhibitors. To improve therapeutic efficacy, natural plant-derived compounds might be considered as potent additives. Here, we show that magnolol, a constituent of Magnolia officinalis, induced G1 arrest, apoptosis and cell death in BRAF- and NRAS-mutant melanoma cells at low concentration, with no effect in BRAF- and NRAS wild-type melanoma cells and human keratinocytes. This was confirmed in a 3D spheroid model. The apoptosis-inducing effect of magnolol was completely rescued by activating Akt suggesting a mechanism relying primarily on Akt signaling. Magnolol significantly downregulated the PI3K/Akt pathway which led to a global decrease of the active histone mark H3K4me3. Alongside, the repressive histone mark H3K9me3 was increased as a response to DNA damage. Magnolol-induced alterations of histone modifications are reversible upon activation of the Akt pathway. Magnolol-induced a synergistic effect in combination with either BRAF/MEK inhibitors dabrafenib/trametinib or docetaxel at a lower concentration than usually applied in melanoma patients. Combination of magnolol with targeted therapy or chemotherapy also led to analogous effects on histone marks, which was rescued by Akt pathway activation. Our study revealed a novel epigenetic mechanism of magnolol-induced cell death in melanoma. Magnolol might therefore be a clinically useful addition to BRAF/MEK inhibitors with enhanced efficacy delaying or preventing disease recurrence.


Assuntos
Compostos de Bifenilo/farmacologia , Epigênese Genética/efeitos dos fármacos , GTP Fosfo-Hidrolases/genética , Lignanas/farmacologia , Proteínas de Membrana/genética , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/genética , Melanoma/metabolismo , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacos
9.
J Surg Oncol ; 119(7): 887-896, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30734295

RESUMO

BACKGROUND AND OBJECTIVES: In-transit melanoma (ITM) metastases present a therapeutic challenge and management decisions can be difficult. There are multiple treatments available, with differing efficacy, and supported by different levels of evidence. The primary objective was to perform a systematic review and where suitable, a meta-analysis of the literature reporting on the use of locoregional treatments for the management of ITM. METHODS: An independent review was conducted including a comprehensive search of the National Library of Medicine using PubMed, MEDLINE, Embase, and Cochrane Library databases. Key data were tabulated, synthesized and pooled to calculate relevant weighted effect sizes for each therapy using random-effect models. The statistical heterogeneity was calculated using the Higgins' method. RESULTS: Of the initial 32 612 articles identified, 57 original articles satisfied eligibility criteria. Eight treatment modalities were identified comprising: amputation (7); hyperthermic isolated limb perfusion (15); isolated limb infusion (8); carbon dioxide laser (9); PV-10 intralesional therapy (5); IL-2 intralesional therapy (8); imiquimod (7); diphenylcyclopropenone (3). Only amputation and topical imiquimod were suitable for formal meta-analysis. CONCLUSIONS: All of the assessed therapies have significant selection bias. Variable levels of evidence support the ongoing use of locoregional treatments and these may significantly improve disease-free survival.


Assuntos
Melanoma/patologia , Melanoma/terapia , Humanos , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Metástase Neoplásica
10.
Australas J Dermatol ; 60(3): e186-e194, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30666627

RESUMO

Calciphylaxis is a rare but life-threatening condition, most commonly affecting patients with stage 4 or 5 chronic kidney disease. No universally accepted therapy exists so far. In an attempt to avoid surgical intervention with parathyroidectomy, which is of questionable efficacy and carries several risks, a number of noninvasive treatments have been trialled with variable success. These treatments are aimed at modifying risk factors for calciphylaxis, in particular hypercalcaemia, hyperphosphataemia and hyperparathyroidism. The aim of this review was to summarise the available evidence to determine the potential role of cinacalcet in the treatment of calciphylaxis in patients with chronic kidney disease. Demographic, clinical and laboratory data were retrospectively collected from the available English and non-English literature. Overall, there was a very high response rate (partial or complete) of calciphylaxis lesions to both cinacalcet monotherapy and cinacalcet as part of a combination therapy (83.4% and 82.8%, respectively). When examining complete response to treatment specifically, combination therapy with cinacalcet proved more efficacious than monotherapy (62.1% versus 41.7%). There was also an associated rapid reduction of intact parathyroid hormone over a period of 2-33 months in both groups. While there are limitations as to how our data can be interpreted due to the heterogeneity of the methods and follow-up of the included case reports and case series, prompt and consistent therapy including cinacalcet may help improve the disease outcome. Additional research needs to be performed in this area, to further define the optimal use of cinacalcet for the treatment of calciphylaxis.


Assuntos
Calciofilaxia/tratamento farmacológico , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Cinacalcete/uso terapêutico , Insuficiência Renal Crônica/complicações , Terapia Combinada , Humanos
11.
J Invest Dermatol ; 139(1): 213-223, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30077724

RESUMO

EGFR overexpression is associated with squamous cell carcinoma development. Altered endocytosis and polarization of receptor tyrosine kinases, including EGFR, affect migration and invasion in three-dimensional culture. These studies have been completed via genetic sequencing, cell line, or three-dimensional in vitro and in vivo murine models. Here, we describe an imaging method that allows ex vivo examination of ligand-induced endocytosis of EGFR in non-dissociated human tumors. We analyzed sets of tumor samples from advanced cutaneous squamous cell carcinoma and head and neck squamous cell carcinoma, actinic keratosis, intraepidermal carcinoma, and cutaneous squamous cell carcinoma. We show that EGFR endocytosis is dysregulated in advanced SCC and correlates with anti-EGFR monoclonal antibody therapy outcomes. In actinic keratosis, intraepidermal carcinoma, and well-differentiated cutaneous squamous cell carcinoma, different patterns of epidermal growth factor ligand uptake and binding were observed at the leading edge of different dysplastic lesions, suggesting that these differences in EGFR endocytosis might influence the metastatic potential of dysplastic squamous epithelium. These studies in live ex vivo human tumors confirm that endocytosis dysregulation is a physiological event in human tumors and has therapeutic implications.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , RNA Neoplásico/genética , Neoplasias Cutâneas/genética , Pele/patologia , Biópsia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Movimento Celular , Receptores ErbB/biossíntese , Receptores ErbB/genética , Humanos , Microscopia Confocal , Reação em Cadeia da Polimerase , Pele/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
13.
BMJ Open ; 8(9): e025857, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232117

RESUMO

INTRODUCTION: Having many melanocytic naevi or 'moles' on the skin is the strongest predictor of melanoma; thus, much can be learnt from investigating naevi in the general population. We aim to improve the understanding of the epidemiology and biology of naevi by conducting a 3-year prospective study of melanocytic naevi in adults. METHODS AND ANALYSIS: This is a population-based cohort study of melanocytic naevi in 200 adults aged 20-69 years recruited via the Australian electoral roll. At baseline, participants will complete a questionnaire on their sun behaviour and health and undergo a clinical examination. Three-dimensional (3D) total-body photography will be used to record the images of skin lesions. Pigmented naevi will be analysed in terms of number, diameter, colour and border irregularity using automated analysis software (excluding scalp, beneath underwear and soles of feet). All naevi ≥5 mm will be recorded using the integrated dermoscopy photographic system. A saliva sample will be obtained at baseline for genomic DNA analysis of pigmentation, naevus and melanoma-associated genes using the Illumina HumanCoreExome platform. The sun behaviour and health follow-up questionnaire, clinical examination and 3D total-body photography will be repeated every 6 months for 3 years. The first 50 participants will also undergo manual counts of naevi ≥2 mm and ≥5 mm at baseline, 6-month and 12-month follow-ups. Microbiopsy and excision of naevi of research interest is planned to commence at the 18-month time point among those who agree to donate samples for detailed histopathological and molecular assessment. ETHICS AND DISSEMINATION: This study was approved by the Metro South Health Human Research Ethics Committee in April 2016 (approval number: HREC/16/QPAH/125). The findings will be disseminated through peer-reviewed and non-peer-reviewed publications and presentations at conferences.


Assuntos
Nevo Pigmentado/diagnóstico por imagem , Nevo Pigmentado/epidemiologia , Projetos de Pesquisa , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Austrália/epidemiologia , Biópsia , Dermoscopia , Testes Genéticos , Comportamentos de Risco à Saúde , Humanos , Pessoa de Meia-Idade , Nevo Pigmentado/genética , Nevo Pigmentado/patologia , Fotografação , Exame Físico , Estudos Prospectivos , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Luz Solar , Inquéritos e Questionários , Carga Tumoral , Adulto Jovem
14.
Oncotarget ; 9(9): 8206-8222, 2018 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-29492189

RESUMO

Besides somatic mutations or drug efflux, epigenetic reprogramming can lead to acquired drug resistance. We recently have identified early stress-induced multi-drug tolerant cancer cells termed induced drug-tolerant cells (IDTCs). Here, IDTCs were generated using different types of cancer cell lines; melanoma, lung, breast and colon cancer. A common loss of the H3K4me3 and H3K27me3 and gain of H3K9me3 mark was observed as a significant response to drug exposure or nutrient starvation in IDTCs. These epigenetic changes were reversible upon drug holidays. Microarray, qRT-PCR and protein expression data confirmed the up-regulation of histone methyltransferases (SETDB1 and SETDB2) which contribute to the accumulation of H3K9me3 concomitantly in the different cancer types. Genome-wide studies suggest that transcriptional repression of genes is due to concordant loss of H3K4me3 and regional increment of H3K9me3. Conversely, genome-wide CpG site-specific DNA methylation showed no common changes at the IDTC state. This suggests that distinct histone methylation patterns rather than DNA methylation are driving the transition from parental to IDTCs. In addition, silencing of SETDB1/2 reversed multi drug tolerance. Alterations of histone marks in early multi-drug tolerance with an increment in H3K9me3 and loss of H3K4me3/H3K27me3 is neither exclusive for any particular stress response nor cancer type specific but rather a generic response.

15.
J Invest Dermatol ; 138(7): 1636-1644, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29476775

RESUMO

The melanoma transformation rate of an individual nevus is very low despite the detection of oncogenic BRAF or NRAS mutations in 100% of nevi. Acquired melanocytic nevi do, however, mimic melanoma, and approximately 30% of all melanomas arise within pre-existing nevi. Using whole-exome sequencing of 30 matched nevi, adjacent normal skin, and saliva we sought to identify the underlying genetic mechanisms for nevus development. All nevi were clinically, dermoscopically, and histopathologically documented. In addition to identifying somatic mutations, we found mutational signatures relating to UVR mirroring those found in cutaneous melanoma. In nevi we frequently observed the presence of the UVR mutation signature compared with adjacent normal skin (97% vs. 10%, respectively). Copy number aberration analysis showed that for nevi with copy number loss of tumor suppressor genes, this loss was balanced by loss of potent oncogenes. Moreover, reticular and nonspecific patterned nevi showed an increased (P < 0.0001) number of copy number aberrations compared with globular nevi. The mutation signature data generated in this study confirms that UVR strongly contributes to nevogenesis. Copy number changes reflect at a genomic level the dermoscopic differences of acquired melanocytic nevi. Finally, we propose that the balanced loss of tumor suppressor genes and oncogenes is a protective mechanism of acquired melanocytic nevi.


Assuntos
Carcinogênese/genética , Nevo Pigmentado/genética , Neoplasias Cutâneas/genética , Raios Ultravioleta/efeitos adversos , Adulto , Idoso , Austrália , Carcinogênese/efeitos da radiação , Variações do Número de Cópias de DNA/efeitos da radiação , Análise Mutacional de DNA , Genes Supressores de Tumor/efeitos da radiação , Humanos , Pessoa de Meia-Idade , Nevo Pigmentado/etiologia , Nevo Pigmentado/patologia , Nevo Pigmentado/cirurgia , Oncogenes/efeitos da radiação , Pele/patologia , Pele/efeitos da radiação , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Sequenciamento Completo do Exoma
16.
Arch Dermatol Res ; 310(2): 117-126, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29214350

RESUMO

Skin fibrosis has been reported in Borrelia burgdorferi infection in Europe, but has been questioned by several authors. The objective of the present study was to examine the interaction of skin fibroblasts with B. burgdorferi sensu stricto B31 (BB) and B. afzelii (BA) in vitro by electron microscopy. We also determined the expression of collagen type I, TGF-ß, FGF-1, calreticulin (CALR), decorin (DCN), and PDGF-α at the mRNA level in Borrelia/fibroblast co-cultures. Intact Borrelia attach to and transmigrate fibroblasts, and undergo cystic transformation outside the fibroblasts. Fibroblasts preserve their vitality and express a prominent granular endoplasmic reticulum, suggesting activated protein synthesis. On two different semi-quantitative real-time PCR assays, BB- and BA/fibroblast co-cultures showed a significant induction of type I collagen mRNA after 2 days compared to fibroblasts (fourfold for BA and 1.8-fold for BB; p < 0.02). In addition, there was a significant upregulation of mRNA expression of TGF-ß, CALR, PDGF-α, and DCN in BA and BB co-cultures compared to control fibroblasts in monolayer cultures after 2 days (p < 0.01). The BA/fibroblast co-culture induced a considerably greater upregulation of collagen and growth factor mRNA compared to BB/fibroblast co-culture. In contrast, a significant down-regulation of FGF-1 (20-fold for BA and 4.5-fold for BB) mRNA expression was detected in co-cultures compared to controls (p < 0.01). The results of the study support the hypothesis that BB sensu lato, and BA in particular, enhances collagen mRNA expression and can stimulate growth factors responsible for increased collagen production.


Assuntos
Borrelia burgdorferi/fisiologia , Colágeno/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , RNA Mensageiro/metabolismo , Pele/patologia , Animais , Borrelia burgdorferi/patogenicidade , Borrelia burgdorferi/ultraestrutura , Linhagem Celular , Células Cultivadas , Técnicas de Cocultura , Regulação para Baixo , Fibroblastos , Fibrose , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Microscopia Eletrônica , Pele/microbiologia , Pele/ultraestrutura , Fator de Crescimento Transformador beta
17.
J Cell Commun Signal ; 12(1): 133-141, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29192388

RESUMO

The enthusiasm about successful novel therapeutic strategies in cancer is often quickly dampened by the development of drug resistance. This is true for targeted therapies using tyrosine kinase inhibitors for EGFR or BRAF mutant cancers, but is also an increasingly recognized problem for immunotherapies. One of the major obstacles of successful cancer therapy is tumor heterogeneity of genotypic and phenotypic features. Historically, drivers for drug resistance have been suspected and found on the genetic level, with mutations either being pre-existing in a subset of cancer cells or emerging de novo to mediate drug resistance. In contrast to that, our group and others identified a non-mutational adaptive response, resulting in a reversible, drug tolerant, slow cycling phenotype that precedes the emergence of permanent drug resistance and is triggered by prolonged drug exposure. More recently, studies described the importance of initially reversible transcriptional reprogramming for the development of acquired drug resistance, identified factors important for the survival of the slow cycling phenotype and investigated the relationship of mutational and non-mutational resistance mechanisms. However, the connection and relative importance of mutational and adaptive drug resistance in relation to the in vitro models at hand and the clinically observed response patterns remains poorly defined. In this review we focus on adaptive intrinsic phenotypic plasticity in cancer cells that leads to the drug tolerant slow cycling state, which eventually transitions to permanent resistance, and propose a general model based on current literature, to describe the development of acquired drug resistance.

18.
Clin Cancer Res ; 24(5): 1090-1102, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196297

RESUMO

Purpose: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult-to-treat RAS-mutant cancer.Experimental Design: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown. In vitro results were confirmed in RAS-mutant xenograft mouse models in vivoResults: The addition of aspirin but not isobutylphenylpropanoic acid (ibruprofen) or celecoxib (Celebrex) significantly increased the in vitro cytotoxicity of sorafenib. Mechanistically, combined exposure resulted in increased BRAF/CRAF dimerization and the simultaneous hyperactivation of the AMPK and ERK pathways. Combining sorafenib with other AMPK activators, such as metformin or A769662, was not sufficient to decrease cell viability due to sole activation of the AMPK pathway. The cytotoxicity of sorafenib and aspirin was blocked by inhibition of the AMPK or ERK pathways through shRNA or via pharmacologic inhibitors of RAF (LY3009120), MEK (trametinib), or AMPK (compound C). The combination was found to be specific for RAS/RAF-mutant cells and had no significant effect in RAS/RAF-wild-type keratinocytes or melanoma cells. In vivo treatment of human xenografts in NSG mice with sorafenib and aspirin significantly reduced tumor volume compared with each single-agent treatment.Conclusions: Combination sorafenib and aspirin exerts cytotoxicity against RAS/RAF-mutant cells by simultaneously affecting two independent pathways and represents a promising novel strategy for the treatment of RAS-mutant cancers. Clin Cancer Res; 24(5); 1090-102. ©2017 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aspirina/farmacologia , Neoplasias/tratamento farmacológico , Sorafenibe/farmacologia , Proteínas ras/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aspirina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Camundongos , Mutação , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Oncotarget ; 8(43): 75675-75686, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-29088901

RESUMO

Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease. Will immunotherapy and combination therapy trials overcome resistance in metastatic melanoma? In an effort to treat resistant disease, new clinical trials evaluating the combination of immunotherapy with other therapies, such as kinase inhibitors, adoptive cell therapy, chimeric CD40 ligand to boost costimulation, or a tumor-specific oncolytic virus enhancing granulocyte macrophage colony-stimulating factor (GM-CSF) expression, are currently underway. Updated studies on the mechanisms of resistance, immune escape and options to reinvigorate immune cells support the continued discovery of new and improved forms of therapy.

20.
BMJ Open ; 7(10): e016816, 2017 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-28988173

RESUMO

INTRODUCTION: Patients with in-transit melanoma metastases present a therapeutic challenge. Complete surgical excision of localised disease is considered as the gold standard; however, surgery is not always acceptable and alternatives are required. Treatment results reported using imiquimod and diphenylcyclopropenone (DPCP) suggest that topical immunotherapies can be used to successfully treat select patients with melanoma metastases. A phase II, randomised, single centre, pilot study was designed to assess the clinical efficacy and safety of DPCP and imiquimod for the treatment of superficial, cutaneous in-transit melanoma metastases. METHODS AND ANALYSIS: This is an open-label, non-superiority, pilot study with no treatment cross-over. Eligible patients are randomised in a 1:1 ratio to receive topical therapy for up to 12 months with a minimum follow-up period of 12 months. The target sample size is 30 patients, with 15 allocated to each treatment arm. The primary endpoint is the number of patients experiencing a complete response of treated lesions as determined clinically using Response Evaluation Criteria in Solid Tumours. This trial incorporates health-related quality of life measures and biological tissue collection for further experimental substudies. The study will also facilitate a health economic analysis. ETHICS AND DISSEMINATION: Approval was obtained from the Human Research Ethics Committee at the participating centre, and recruitment has commenced. The results of this study will be submitted for formal publication within a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Prospectively registered on 16 October 2015 with the Australian New Zealand Clinical Trials Registry (ACTRN12615001088538). This study conforms to WHO Trial Registration Data Set.


Assuntos
Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Ciclopropanos/uso terapêutico , Imunoterapia , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Administração Tópica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos Clínicos , Feminino , Humanos , Imiquimode , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Indução de Remissão , Projetos de Pesquisa , Resultado do Tratamento , Adulto Jovem
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