BACKGROUND: Metastatic malignant melanoma belongs to a group of cancers with high mortality. In recent years, advances in our knowledge of the pathogenesis of melanoma and the discovery of new drugs has resulted in significant progress in the treatment of metastatic malignant melanoma patients. The development of resistance to these drugs, however, remains a challenge. One way how to avoid resistance, or at least delay it, is to administer combination therapy. OBSERVATION AND CONCLUSION: This case study demonstrates that combination therapy with a BRAF and a MEK inhibitor can be used to successfully treat metastatic malignant melanoma patients and suggests they should be employed in therapeutic algorithms for patients with metastatic malignant melanoma and BRAF gene mutations.

• MeSH
• imidazoly aplikace a dávkování   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• melanom farmakoterapie   patologie   MeSH
• metastázy nádorů MeSH
• mitogenem aktivované proteinkinasy kinas antagonisté a inhibitory   MeSH
• oximy aplikace a dávkování   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf antagonisté a inhibitory   MeSH
• pyridony aplikace a dávkování   MeSH
• pyrimidinony aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dabrafenib MeSH Prohlížeč
• imidazoly MeSH
• inhibitory proteinkinas MeSH
• mitogenem aktivované proteinkinasy kinas MeSH
• oximy MeSH
• protoonkogenní proteiny B-Raf MeSH
• pyridony MeSH
• pyrimidinony MeSH
• trametinib MeSH Prohlížeč

The incidence of malignant melanoma is increasing worldwide, despite our best efforts in prevention and early detection. The locally advanced disease may be treated surgically with good results, however, metastatic melanoma is considered to be one of the most therapeutically challenging malignancies. The increasing knowledge of molecular changes in melanoma may change this picture. Malignant melanoma is not a singular, homogeneous disease but rather a mixture of subtypes characterized by specific mutations. Tumors with C-KIT mutation respond to therapy with C-KIT kinase inhibitor imatinib and the ones characterized by BRAF mutations respond to BRAF kinase inhibitor vemurafenib. Vemurafenib was approved by US FDA in 2011 and EMA in 2012 for therapy of patients with advanced melanoma, harboring mutation in BRAFV600E gene. Ipilimumab, an antibody to cytotoxic T-lymphocyte antigen 4 (CTLA-4), was registered in 2011 by both US FDA and European Medicines Agency for treatment of metastatic melanoma. This therapy promotes the anti-tumor T-cell activity by blocking a CTLA-4 antigen, a key negative regulator of immune response.

• MeSH
• cílená molekulární terapie * MeSH
• indoly škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• melanom imunologie   sekundární   terapie   MeSH
• mutace * MeSH
• nádory kůže imunologie   terapie   MeSH
• protein vázající fosfatidylethanolamin škodlivé účinky   terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf antagonisté a inhibitory   genetika   MeSH
• sulfonamidy škodlivé účinky   terapeutické užití   MeSH
• vemurafenib MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• indoly MeSH
• protein vázající fosfatidylethanolamin MeSH
• protoonkogenní proteiny B-Raf MeSH
• sulfonamidy MeSH
• vemurafenib MeSH

BACKGROUND: Worldwide metastatic colorectal cancer is the second most common cause of death attributable to cancer. Advances in molecular dia-gnostics led to recognition of several molecular subtypes of this disease. BRAF mutated colorectal cancer define specific challenging subgroup associated with dismal prognosis, lower rate of response rate, shorter progression free survival and overall survival. Current treatment choices are associated with poor outcomes. For the first line treatment doublet or triplet chemotherapy plus antiangiogenic antibody is used. To date, there were no reasonable treatment options in the second line settings. Recently published BEACON trial sets new standard of treatment with combination of encorafenib plus cetuximab, which led to significantly longer overall survival and overall response compared to standard therapy. Furthermore, this combination has shown well-tolerated safety profile with manageable toxicities. PURPOSE: The aim of this article is a review of current treatment options for BRAF mutated colorectal cancer.

• Klíčová slova
• BEACON, BRAF V600E, binimetinib, cetuximab, encorafenib, metastatic colorectal cancer,
• MeSH
• cetuximab aplikace a dávkování   MeSH
• karbamáty aplikace a dávkování   MeSH
• kolorektální nádory farmakoterapie   genetika   mortalita   patologie   MeSH
• lidé MeSH
• mutace MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf antagonisté a inhibitory   genetika   MeSH
• sulfonamidy aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• cetuximab MeSH
• encorafenib MeSH Prohlížeč
• karbamáty MeSH
• protoonkogenní proteiny B-Raf MeSH
• sulfonamidy MeSH

BACKGROUND: Activating BRAF mutations result in constitutive activation of the MAP kinase signaling cascade, stimulating cell proliferation. BRAF mutations are typical for malignant melanoma, but occur less frequently in other tumors, including in 1-2% cases of non-small cell lung cancer (NSCLC) [1,2]. CASE: We present two case reports of BRAF+ NSCLC patients, treated with 3rd line dabrafenib monotherapy on our department, and also brief review of available information about dabrafenib and its use in monotherapy of BRAF+ NSCLC. CONCLUSION: Monotherapy with BRAF inhibitors presents a viable alternative for BRAF+ NSCLC patients, incapable of combined therapy with trametinib. The lack of proper indication and reimbursement for NSCLC cases remains a problem, and individual treatment approval is required.

• Klíčová slova
• dabrafenib – BRAF – lung cancer – non-small cell – NSCLC – monotherapy,
• MeSH
• antitumorózní látky terapeutické užití   MeSH
• imidazoly terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádory plic farmakoterapie   genetika   MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   MeSH
• oximy terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antitumorózní látky MeSH
• dabrafenib MeSH Prohlížeč
• imidazoly MeSH
• inhibitory proteinkinas MeSH
• oximy MeSH
• protoonkogenní proteiny B-Raf MeSH

AIM: The aim is to assess the BRAF gene mutations in patients with posterior uveal melanoma. MATERIAL AND METHODS: Retrospective analysis of the group of patients with malignant melanoma of the uvea, who were indicated to enucleation between 1.1 2015 to 1.3.2016. We analyzed stage of uveal melanoma, volume, cell type and BRAF gene mutations. RESULTS: In clinical study of 20 patients after enucleation due to uveal melanoma at the Department of Ophthalmology in Bratislava, patient age was ranged from 22 to 89 years with a median of 62 years. In 14 patients (70 %) enucleation was the primary treatment and in 6 patients (30 %) enucleation was after irradiation (brachytherapy, Leksell gama knife, linear accelerator). In 17 cases (85 %) the mutation of the BRAF gene was negative and in 3 cases the sample was not assessable for the BRAF mutation. CONCLUSION: BRAF gene mutation is confirmed by several studies found in malignant melanoma of the skin. The histopathology findings in our group did not confirmed our theory, that since the uveal melanoma itself has the similar origin as skin melanoma, should also contain a BRAF mutation.Key words: malignant melanoma of the uvea, mutation of the BRAF gene, chromosomal abnormalities as a prognostic factor.

• MeSH
• brachyterapie MeSH
• dospělí MeSH
• enukleace oka MeSH
• lidé středního věku MeSH
• lidé MeSH
• maligní melanom kůže MeSH
• melanom genetika   patologie   chirurgie   MeSH
• metastázy nádorů genetika   MeSH
• mladý dospělý MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• nádorové biomarkery genetika   MeSH
• nádory kůže genetika   patologie   MeSH
• nádory uvey genetika   patologie   chirurgie   MeSH
• prognóza MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• protoonkogenní proteiny B-Raf MeSH

BACKGROUND: MicroRNAs (miRNAs) are non-coding regulatory molecules 18-25 nucleotides in length that act as post-transcriptional regulators of gene expression. MiRNAs affect various biological processes including carcinogenesis. Deregulation of miRNAa expression has been described in a variety of tumors including papillary thyroid carcinoma (PTC). The aim of the present study was to investigate the role of selected miRNAs in PTC and find associations between miRNA expression and the BRAF (V600E) mutation. MATERIALS AND METHODS: The study group comprised a total of 62 patients with surgically treated PTC. The control group consisted of 30 patients with nodular goitre that were surgically treated in the same time period. The expression status of miR-146b, miR-181a, miR-187, miR-221 and miR-222 was determined using quantitative real-time PCR. BRAF mutation analysis was performed by PCR with reverse hybridization. RESULTS: MiR-146b, miR-181a, miR-187, miR-221 and miR-222 were up-regulated in PTC compared to normal thyroid gland tissue of the same patient. MiR-146b, miR-187, miR-221 and miR-222 were also up-regulated in PTC compared to nodular goitre. The recurrent tumors were statistically significantly associated with up-regulation of miR-221. The mutation V600E of BRAF gene was significantly associated with up-regulation of miR-146b and with down-regulation of miR-187. CONCLUSION: Over-expression of selected miRNAs in PTC compared to normal thyroid gland tissue and nodular goitre was found. Moreover, miR-221 may serve as a prognostic marker as its over-expression was significantly associated with recurrent tumors.

• Klíčová slova
• BRAF mutation, MicroRNA, papillary thyroid cancer,
• MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• mikro RNA * genetika   MeSH
• mutace MeSH
• nádory štítné žlázy * genetika   MeSH
• papilární karcinom štítné žlázy genetika   MeSH
• papilární karcinom * genetika   MeSH
• prognóza MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• mikro RNA * MeSH
• protoonkogenní proteiny B-Raf MeSH

BACKGROUND: Targeted biological therapy based on blocking growth factor receptors and inhibition of cancer-inducing signaling pathways is a new treatment facility for patients with colorectal cancer (CRC). Therapeutic agents are monoclonal antibodies targeting epidermal growth factor receptor (EGFR). Gene aberrations in the EGFR-induced pathways are negative predictors of therapeutic response. Determination of -non-mutated KRAS is a requirement for the indication of targeted anti-EGFR therapy in the present time, BRAF mutation analysis is recommended. Comparison of our results with published data and verification of routine laboratory methods in relation to diagnostic kits were the purposes of this study. PATIENTS AND METHODS: In addition to routine methods based on PCR, direct sequencing as well as two diagnostic kits for KRAS (codon 12 and 13) and BRAF (codon 600) mutation analysis were used for 132 patients. RESULTS: KRAS mutations were detected in 45 patients (34%), V600E mutation of the BRAF gene in 9 patients (7%). Both mutations simultaneously were not detected. Tissues from primary tumor and metastases were available from 33 patients. KRAS mutation was detected in 13 cases of this group. KRAS mutations in tumor and metastasis were of the same type in 9 patients; types of mutation in both tissues were different in one case. KRAS mutation only in one tissue was detected in 3 cases. BRAF mutation in both tissues was detected in the 4 patients. A low percentage of tumor cells in 17 patients specimen did not allow performance of routine analysis and diagnostic kit was used. CONCLUSION: The frequency of KRAS and BRAF mutations in our cohort of patients corresponds to published data. The suitability of metastatic tissue analysis due to tumor heterogeneity was confirmed. KRAS analysis requires a comprehensive methodological approach with regard to reduced DNA quality and different percentage of tumor cells in tissue. For this reason, commercial diagnostic kits constitute a suitable supplement to standard methods.

• MeSH
• cílená molekulární terapie MeSH
• kolorektální nádory genetika   terapie   MeSH
• lidé MeSH
• mutace * MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• protoonkogenní proteiny p21(ras) MeSH
• protoonkogenní proteiny genetika   MeSH
• Ras proteiny genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• KRAS protein, human MeSH Prohlížeč
• protoonkogenní proteiny B-Raf MeSH
• protoonkogenní proteiny p21(ras) MeSH
• protoonkogenní proteiny MeSH
• Ras proteiny MeSH

The identification of the V600E activating mutation in the protein kinase BRAF in around 50% of melanoma patients has driven the development of highly potent small inhibitors (BRAFi) of the mutated protein. To date, Dabrafenib and Vemurafenib, two specific BRAFi, have been clinically approved for the treatment of metastatic melanoma. Unfortunately, after the initial response, tumors become resistant and patients develop a progressive and lethal disease, making imperative the development of new therapeutic options. The main objective of this work was to find new BRAF inhibitors with different structural scaffolds than those of the known inhibitors. Our study was carried out in different stages; in the first step we performed a virtual screening that allowed us to identify potential new inhibitors. In the second step, we synthesized and tested the inhibitory activity of the novel compounds founded. Finally, we conducted a molecular modelling study that allowed us to understand interactions at the molecular level that stabilize the formation of the different molecular complexes. Our theoretical and experimental study allowed the identification of four new structural scaffolds, which could be used as starting structures for the design and development of new inhibitors of BRAF. Our experimental data indicate that the most active compounds reduced significantly ERK½ phosphorylation, a measure of BRAF inhibition, and cell viability. Thus, from our theoretical and experimental results, we propose new substituted hydroxynaphthalenecarboxamides, N-(hetero)aryl-piperazinylhydroxyalkylphenylcarbamates, substituted piperazinylethanols and substituted piperazinylpropandiols as initial structures for the development of new inhibitors for BRAF. Moreover, by performing QTAIM analysis, we are able to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analysis indicates which portion of the different molecules must be changed in order to obtain an increase in the binding affinity of these new ligands.

• Klíčová slova
• BRAF inhibitors, Bioassays, Molecular modeling, Synthesis, Virtual screening,
• MeSH
• antitumorózní látky chemická syntéza   metabolismus   farmakologie   MeSH
• inhibitory proteinkinas chemická syntéza   metabolismus   farmakologie   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• protoonkogenní proteiny B-Raf antagonisté a inhibitory   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vemurafenib farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• BRAF protein, human MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• protoonkogenní proteiny B-Raf MeSH
• vemurafenib MeSH

The oncogenic mutated kinase BRAFV600E is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although many protocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness because patients invariably develop resistance and secondary toxic effects associated with the therapy. These limitations highlight the importance of designing new and better inhibitors with different structures that could establish different interactions in the active site of the enzyme and therefore decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, by establishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results we synthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAFV600E inhibitors possessing this type of structural scaffold.

• Klíčová slova
• BRAF inhibitors, Cell viability, ERK phosphorylation, Melanoma, Molecular modeling,
• MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• fosforylace MeSH
• lidé MeSH
• melanom farmakoterapie   MeSH
• molekulární modely MeSH
• protoonkogenní proteiny B-Raf antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• protoonkogenní proteiny B-Raf MeSH

PURPOSE: To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). PATIENTS AND METHODS: This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). RESULTS: The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. CONCLUSION: This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

• MeSH
• dospělí MeSH
• hodnocení rizik metody   statistika a číselné údaje   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• missense mutace * MeSH
• nádory štítné žlázy genetika   patologie   MeSH
• následné studie MeSH
• papilární karcinom genetika   patologie   MeSH
• prognóza MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• protoonkogenní proteiny B-Raf MeSH