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https://www.readbyqxmd.com/read/28102344/predicting-drug-combination-index-and-simulating-the-network-regulation-dynamics-by-mathematical-modeling-of-drug-targeted-egfr-erk-signaling-pathway
#1
Lu Huang, Yuyang Jiang, Yuzong Chen
Synergistic drug combinations enable enhanced therapeutics. Their discovery typically involves the measurement and assessment of drug combination index (CI), which can be facilitated by the development and applications of in-silico CI predictive tools. In this work, we developed and tested the ability of a mathematical model of drug-targeted EGFR-ERK pathway in predicting CIs and in analyzing multiple synergistic drug combinations against observations. Our mathematical model was validated against the literature reported signaling, drug response dynamics, and EGFR-MEK drug combination effect...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28101205/impact-of-microsatellite-status-on-chemotherapy-for-colorectal-cancer-patients-with-kras-or-braf-mutation
#2
Chi-Jung Huang, Shih-Hung Huang, Chih-Cheng Chien, Henry Hsin-Chung Lee, Shung-Haur Yang, Chun-Chao Chang, Chia-Long Lee
KRAS and BRAF mutations are frequently detected in cases of colorectal cancer (CRC). The microsatellite status of patients with CRC and mutated KRAS/BRAF is important when determining cancer therapy. In the present study, the microsatellite status and genetic polymorphisms of KRAS (codons 12 and 13) and BRAF (V600E) were characterized in CRC tissue. The mismatch repair activity and oncogenic potential of KRAS were assessed by immunoblots from two KRAS-mutated CRC cell lines, SW480 and HCT116, with different microsatellite statuses, following treatment with 5-fluorouracil (5-FU) and oxaliplatin...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28099366/does-the-distribution-pattern-of-brain-metastases-during-braf-inhibitor-therapy-reflect-phenotype-switching
#3
Silvia A Haueis, Pascale Kränzlin, Joanna Mangana, Phil F Cheng, Mirjana Urosevic-Maiwald, Ralph P Braun, Mitchell P Levesque, Reinhard Dummer, Simone M Goldinger
Brain metastases (brain mets) are frequent in metastatic melanoma patients. The aim of this study was to investigate the morphology and progression pattern of brain mets in melanoma patients treated with BRAF inhibitors (BRAFi) compared with patients who did not receive targeted therapy (BRAFi group and control group). The number and size of brain mets were compared between a baseline and a comparative MRI at progression. The number of brain mets was grouped into seven number classes (N=1-4, N=5-10, N=11-20, N=21-30, N=31-40, N=41-50, and N>50) and its difference was reported as the change of class that occurred...
January 17, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28099231/vemurafenib-braf-inhibitor-therapy-for-orbital-erdheim-chester-disease
#4
Adit Gupta, Amir Yeganeh, Daniel Rootman, Robert Goldberg
Erdheim-Chester disease is a rare xanthogranulomatous systemic disease, which involves the orbit in some cases. Through this case report, the authors review the treatment modalities used in orbital Erdheim-Chester disease and explore a newer modality of treatment. Cases of orbital Erdheim-Chester disease were identified in the literature utilizing a PubMed search and all the treatment modalities were reviewed. The response to treatment of orbital Erdheim-Chester disease has been poor with the various medical and surgical treatment modalities used in the past...
January 17, 2017: Ophthalmic Plastic and Reconstructive Surgery
https://www.readbyqxmd.com/read/28098915/somatic-mutational-spectrum-analysis-in-a-prospective-series-of-104-gastrointestinal-stromal-tumors
#5
David Guenat, Olivier Deroo, Sandrine Magnin, Loïc Chaigneau, Franck Monnien, Christophe Borg, Christiane Mougin, Jean-François Emile, Jean-Luc Prétet
Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors distinguished by driver mutations in proto-oncogenes KIT or PDGFRA in 85-90% of cases. These mutations have been linked to the response to imatinib, a multikinase inhibitor, and have independent prognostic impact. Here, we describe the prospective study of the molecular characteristics of 104 GISTs from French adult patients analyzed routinely through the National Hospital Program of Molecular Cancer Diagnosis. All patients with GISTs diagnosed at the University Hospital of Besançon between August 2005 and October 2014 were prospectively included in the present study...
January 17, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28098866/in-vitro-long-term-treatment-with-mapk-inhibitors-induces-melanoma-cells-with-resistance-plasticity-to-inhibitors-while-retaining-sensitivity-to-cd8-t-cells
#6
Florencia Paula Madorsky Rowdo, Antonela Barón, Erika María von Euw, José Mordoh
The development of BRAF V600 and MEK inhibitors constitutes a breakthrough in the treatment of patients with BRAF-mutated metastatic melanoma. However, although there is an increase in overall survival, these patients generally confront recurrence, and several resistance mechanisms have already been described. In the present study we describe a different resistance mechanism. After several weeks of long‑term in vitro treatment of two different V600E BRAF‑mutated melanoma cell lines with MARK inhibitors, PLX4032 and/or GDC-0973, the majority of the cells died whereas some remained viable and quiescent (SUR)...
January 13, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28097802/genomic-analysis-and-clinical-management-of-adolescent-cutaneous-melanoma
#7
Roy Rabbie, Mamun Rashid, Ana M Arance, Marcelo Sánchez, Gemma Tell-Marti, Miriam Potrony, Carles Conill, Remco van Doorn, Stefan Dentro, Nellele A Gruis, Pippa Corrie, Vivek Iyer, Carla Daniela Robles-Espinoza, Joan A Puig-Butille, Susana Puig, David J Adams
Melanoma in young children is rare, however its incidence in adolescents and young adults is rising. We describe the clinical course of a 15-year-old female diagnosed with AJCC stage IB non-ulcerated primary melanoma, who died from metastatic disease four years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas, and 275 adult cutaneous melanomas. A somatic BRAF(V)(600E) mutation and a high mutational load equivalent to that found in adult melanoma, and composed primarily of C>T mutations was observed...
January 17, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28097409/genetic-and-epigenetic-intra-tumour-heterogeneity-in-colorectal-cancer
#8
Huw Geraint Jones, Gareth Jenkins, Namor Williams, Paul Griffiths, Phil Chambers, John Beynon, Dean Harris
INTRODUCTION: Colorectal cancer (CRC) is a highly heterogeneous disease, with pathologically similar cancers having completely different responses to treatment and patient survival. Intra-tumour heterogeneity (defined as distinct morphological and phenotypic differences) has recently been demonstrated to be an important factor in the development and behaviour of cancer cells and can be used to determine response to anticancer therapy. METHOD: Patients with resected CRC had DNA extracted from eight defined tumour areas which were analysed for two genetic mutations (BRAF and KRAS) and one epigenetic trait (CpG island methylator phenotype/CIMP)...
January 17, 2017: World Journal of Surgery
https://www.readbyqxmd.com/read/28096700/sequential-combination-chemotherapy-of-dacarbazine-dtic-with-carboplatin-and-paclitaxel-for-patients-with-metastatic-mucosal-melanoma-of-nasal-cavity-and-paranasal-sinuses
#9
W Omata, A Tsutsumida, K Namikawa, A Takahashi, K Oashi, N Yamazaki
By the recent introduction of molecular targeting drugs against BRAF mutation and immune checkpoint inhibitors, the prognosis of patients with melanoma in advanced stage is now improving, but still in the minority. Mucosal melanoma lacks the BRAF mutations, and hence conventional chemotherapeutic regimens must be improved. We have conventionally used dacarbazine (DTIC) for patients with metastatic mucosal melanoma. However, the efficacy of DTIC in patients with metastatic mucosal melanoma has been limited. Therefore, we explored other possibilities to improve the prognosis of patients suffering from metastatic mucosal melanoma...
2017: Clinical Medicine Insights. Case Reports
https://www.readbyqxmd.com/read/28094001/autophagy-inhibition-overcomes-multiple-mechanisms-of-resistance-to-braf-inhibition-in-brain-tumors
#10
Jean M Mulcahy Levy, Shadi Zahedi, Andrea M Griesinger, Andrew Morin, Kurtis D Davies, Dara L Aisner, B K Kleinschmidt-DeMasters, Brent E Fitzwalter, Megan L Goodall, Jacqueline Thorburn, Vladimir Amani, Andrew M Donson, Diane K Birks, David M Mirsky, Todd C Hankinson, Michael H Handler, Adam L Green, Rajeev Vibhakar, Nicholas K Foreman, Andrew Thorburn
Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAF(V600E)mutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAF(V600E) inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance...
January 17, 2017: ELife
https://www.readbyqxmd.com/read/28093501/discrete-cytosolic-macromolecular-braf-complexes-exhibit-distinct-activities-and-composition
#11
Britta Diedrich, Kristoffer Tg Rigbolt, Michael Röring, Ricarda Herr, Stephanie Kaeser-Pebernard, Christine Gretzmeier, Robert F Murphy, Tilman Brummer, Jörn Dengjel
As a central element within the RAS/ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. Consequently, it has emerged as an important therapeutic target in various malignancies. Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. By applying SEC-PCP-SILAC, we analyzed protein-protein interactions of hyperactive BRAF(V)(600E) and wild-type BRAF (BRAF(WT))...
January 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28093487/a-pilot-trial-of-the-combination-of-vemurafenib-with-adoptive-cell-therapy-in-patients-with-metastatic-melanoma
#12
Drew C Deniger, Mei Li M Kwong, Anna Pasetto, Mark E Dudley, John R Wunderlich, Michelle M Langhan, Chyi-Chia Richard Lee, Steven A Rosenberg
PURPOSE: This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF(V600) mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. EXPERIMENTAL DESIGN: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration...
January 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28093480/comprehensive-screening-for-pd-l1-expression-in-thyroid-cancer
#13
Soomin Ahn, Tae Hyuk Kim, Sun Wook Kim, Chang Seok Ki, Hye Won Jang, Jee Soo Kim, Jung Han Kim, Jun-Ho Choe, Jung Hee Shin, Soo Yeon Hahn, Young Lyun Oh, Jae Hoon Chung
PD-L1 expression is being considered a potential biomarker for response of anti-PD-1 or anti-PD-L1 agents in various tumors. The reported frequency of PD-L1 positivity varies in thyroid carcinomas, and multiple factors may contribute to the variability in PD-L1 positivity. We evaluated the PD-L1 expression in various thyroid cancers on a large scale. A total of 407 primary thyroid cancers with a median 13.7-year of follow-up were included. We evaluated the frequency of PD-L1 expression using a rabbit monoclonal antibody (clone SP142)...
February 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28093345/stereotactic-radiosurgery-srs-for-melanoma-brain-metastases-a-comprehensive-clinical-case-series
#14
Rui Feng, Eric K Oermann, Raj Shrivastava, Ariel Gold, Brian T Collins, Douglas Kondziolka, Sean P Collins
BACKGROUND: Melanoma has high propensity to metastasize to the brain. With recent gains in improving patient survival, stereotactic radiosurgery may offer an effective and less neurotoxic alternative to whole brain radiation. In the study, we report on the safety and efficacy of stereotactic radiosurgery (SRS) in treating melanoma brain metastases in 87 patients. METHODS: This retrospective, multicenter study examined 87 patients with 309 metastases underwent single-dose or multifractionated SRS for treatment of intracranial metastases from malignant melanoma...
January 13, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28092671/pde4d-promotes-fak-mediated-cell-invasion-in-braf-mutated-melanoma
#15
J Delyon, A Servy, F Laugier, J André, N Ortonne, M Battistella, S Mourah, A Bensussan, C Lebbé, N Dumaz
The cyclic AMP (cAMP) signaling pathway is critical in melanocyte biology for regulating differentiation. It is downregulated by phosphodiesterase (PDE) enzymes, which degrade cAMP itself. In melanoma evidence suggests that inhibition of the cAMP pathway by PDE type 4 (PDE4) favors tumor progression. For example, in melanomas harboring RAS mutations, the overexpression of PDE4 is crucial for MAPK pathway activation and proliferation induced by oncogenic RAS. Here we showed that PDE4D is overexpressed in BRAF-mutated melanoma cell lines, constitutively disrupting the cAMP pathway activation...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28092667/oncogenic-braf-fusions-in-mucosal-melanomas-activate-the-mapk-pathway-and-are-sensitive-to-mek-pi3k-inhibition-or-mek-cdk4-6-inhibition
#16
H S Kim, M Jung, H N Kang, H Kim, C-W Park, S-M Kim, S J Shin, S H Kim, S G Kim, E K Kim, M R Yun, Z Zheng, K Y Chung, J Greenbowe, S M Ali, T-M Kim, B C Cho
Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28091917/detection-of-rare-mutations-by-routine-analysis-of-kras-nras-and-braf-oncogenes
#17
D S Mikhailenko, G D Efremov, N Yu Safronova, V V Strelnikov, B Ya Alekseev
Molecular genetic analysis of KRAS, NRAS, and BRAF genes was carried out in order to develop an optimal algorithm for detection of minor mutations. We analyzed 35 melanoma and 33 colorectal cancer specimens. Frequent G12D/V/A/C/S mutations were detected in KRAS. The most frequent BRAF mutation in melanoma was V600E, the percentage of rare mutations is significant for DNA diagnosis (24%). Identification of rare BRAF mutations 1790C→G (L597R), 1798_1799delinsAA (V600K), 1798_1799delinsAG (V600R), and 1799_1800delinsAA (V600E) and NRAS mutation 38G→T (G13V) was possible only by Sanger sequencing...
January 2017: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28090518/clinical-characteristics-and-molecular-pathology-of-skull-ectopic-thyroid-cancer
#18
Longxing Cao, Zhongyong Wang, Jiawei Ma, Jinsheng Chen, Haojiang Zhu, Xiaohua Zhou, Qing Zhu, Jun Dong, Qing Lan, Qiang Huang
Thyroid cancer is very common, but skull ectopic thyroid cancer has not been reported in 50 years of literatures in foreign countries. There are only four cases of the skull ectopic thyroid cancer reported in more than 30 years of domestic literature including the cases in this report. This paper aims to investigate the clinical characteristics and possible molecular mechanisms of this rare disease. Five keywords of "thyroid gland", "ectopic thyroid", "thyroid cancer", "ectopic thyroid cancer" and "metastatic thyroid cancer" were included and 50 years of literatures in the PubMed-MEDLINE and Wanfang database were reviewed...
December 2016: Annals of Translational Medicine
https://www.readbyqxmd.com/read/28089820/deregulated-expression-of-vhl-mrna-variants-in-papillary-thyroid-cancer
#19
Enke Baldini, Chiara Tuccilli, Yannick Arlot-Bonnemains, Frank Chesnel, Salvatore Sorrenti, Corrado De Vito, Antonio Catania, Eleonora D'Armiento, Alessandro Antonelli, Poupak Fallahi, Sara Watutantrige-Fernando, Francesco Tartaglia, Susi Barollo, Caterina Mian, Marco Bononi, Stefano Arceri, Domenico Mascagni, Massimo Vergine, Daniele Pironi, Massimo Monti, Angelo Filippini, Salvatore Ulisse
Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI)...
January 12, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28089569/prevention-of-dietary-fat-fueled-ketogenesis-attenuates-braf-v600e-tumor-growth
#20
Siyuan Xia, Ruiting Lin, Lingtao Jin, Liang Zhao, Hee-Bum Kang, Yaozhu Pan, Shuangping Liu, Guoqing Qian, Zhiyu Qian, Evmorfia Konstantakou, Baotong Zhang, Jin-Tang Dong, Young Rock Chung, Omar Abdel-Wahab, Taha Merghoub, Lu Zhou, Ragini R Kudchadkar, David H Lawson, Hanna J Khoury, Fadlo R Khuri, Lawrence H Boise, Sagar Lonial, Benjamin H Lee, Brian P Pollack, Jack L Arbiser, Jun Fan, Qun-Ying Lei, Jing Chen
Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice...
January 9, 2017: Cell Metabolism
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