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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/28098866/in-vitro-long-term-treatment-with-mapk-inhibitors-induces-melanoma-cells-with-resistance-plasticity-to-inhibitors-while-retaining-sensitivity-to-cd8-t-cells
#2
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/28092667/oncogenic-braf-fusions-in-mucosal-melanomas-activate-the-mapk-pathway-and-are-sensitive-to-mek-pi3k-inhibition-or-mek-cdk4-6-inhibition
#3
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/28078189/dabrafenib-and-trametinib-activity-in-a-patient-with-braf-v600e-mutated-and-microsatellite-instability-high-msi-h-metastatic-endometrial-cancer
#4
Michele Moschetta, Gabriel Mak, Joana Hauser, Catriona Davies, Mario Uccello, Hendrik-Tobias Arkenau
BACKGROUND: Targeting BRAF V600E mutation has been proven effective in the treatment of several types of cancer. In endometrial adenocarcinoma, the BRAF V600E mutation has been rarely reported. Whether targeting BRAF oncogene may represent a plausible therapeutic strategy for the rare patients with BRAF-mutated endometrial cancer remains to be ascertained in prospective studies. CASE PRESENTATION: We report herein the case of a heavily pre-treated patient with recurrent microsatellite instability high (MSI-H) BRAF V600E mutated endometrial adenocarcinoma, which was successfully treated with the V600E targeting agent dabrafenib...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28078132/impressive-response-to-dual-braf-and-mek-inhibition-in-patients-with-braf-mutant-intrahepatic-cholangiocarcinoma-2-case-reports-and-a-brief-review
#5
Viraj Lavingia, Marwan Fakih
Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced stage and is associated with a poor oncological outcome. The median survival for metastatic ICC is less than 1 year with standard chemotherapy. ICC is associated with distinct oncogenic drivers including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B), which may benefit from matching targeted therapies. Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors (dabrafenib and trametinib) with excellent clinical and radiological response to therapy and with protracted duration of disease control...
December 2016: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28069929/genomic-alterations-of-adamantinomatous-and-papillary-craniopharyngioma
#6
Tobias Goschzik, Marco Gessi, Verena Dreschmann, Ursel Gebhardt, Linghua Wang, Shigeru Yamaguchi, David A Wheeler, Libero Lauriola, Ching C Lau, Hermann L Müller, Torsten Pietsch
Craniopharyngiomas are rare histologically benign but clinically challenging neoplasms. To obtain further information on the molecular genetics and biology of craniopharyngiomas, we analyzed a cohort of 121 adamantinomatous and 16 papillary craniopharyngiomas (ACP, PCP). We extracted DNA from formalin-fixed paraffin-embedded tissue and determined mutational status of CTNNB1, BRAF, and DDX3X by Sanger sequencing, next generation panel sequencing, and pyrosequencing. Sixteen craniopharyngiomas were further analyzed by molecular inversion profiling (MIP); 76...
January 9, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28069687/adaptive-resistance-of-melanoma-cells-to-raf-inhibition-via-reversible-induction-of-a-slowly-dividing-de-differentiated-state
#7
Mohammad Fallahi-Sichani, Verena Becker, Benjamin Izar, Gregory J Baker, Jia-Ren Lin, Sarah A Boswell, Parin Shah, Asaf Rotem, Levi A Garraway, Peter K Sorger
Treatment of BRAF-mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly...
January 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28068326/klf4-is-regulated-by-ras-raf-mek-erk-signaling-through-e2f1-and-promotes-melanoma-cell-growth
#8
M Riverso, V Montagnani, B Stecca
Melanoma is the most lethal form of skin cancer and treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors show only temporary benefit due the occurrence of resistance and immunotherapy is effective only in a subset of patients. To improve patient survival, there is a need to better understand molecular mechanisms that drive melanoma growth and operate downstream of the mitogen activated protein kinase (MAPK) signaling. The Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays a critical role in embryonic development, stemness and cancer, where it can act either as oncogene or tumor suppressor...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28067893/vemurafenib-and-trametinib-reduce-expression-of-ctgf-and-il-8-in-v600e-braf-melanoma-cells
#9
Mariusz L Hartman, Michal Rozanski, Marta Osrodek, Izabela Zalesna, Malgorzata Czyz
Clinical evidence has revealed that while RAS/RAF/MEK/ERK pathway is a crucial component of melanomagenesis, other signaling pathways can also contribute to the malignant growth and development of resistance to targeted therapies. We explored the response of (V600E)BRAF melanoma cells derived from surgical specimens and grown in stem cell medium to vemurafenib and trametinib, drugs targeting the activity of (V600E)BRAF and MEK1/2, respectively. Cell growth and apoptosis were monitored by real-time imaging system, immunophenotype and cell cycle by flow cytometry, gene expression by quantitative real-time PCR, immunoblotting and enzyme-linked immunosorbent assay...
January 9, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28062115/genotype-matched-treatment-for-patients-with-advanced-type-i-epithelial-ovarian-cancer-eoc
#10
A Spreafico, A M Oza, B A Clarke, H J Mackay, P Shaw, M Butler, N C Dhani, S Lheureux, M K Wilson, S Welch, T Zhang, C Yu, T Stockley, L L Siu, S Kamel-Reid, P L Bedard
BACKGROUND: Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program. MATERIAL AND METHODS: Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel...
January 3, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28058658/combination-treatment-of-patients-with-braf-mutant-melanoma-a-new-standard-of-care
#11
REVIEW
Ester Simeone, Antonio M Grimaldi, Lucia Festino, Vito Vanella, Marco Palla, Paolo A Ascierto
Raf-mitogen-activated protein kinase (Raf-MAPK) pathway inhibition with the BRAF inhibitors vemurafenib and dabrafenib, alone or in combination with a MEK inhibitor, has become a standard therapeutic approach in patients with BRAF-mutated metastatic melanoma. Both vemurafenib and dabrafenib have shown good safety and efficacy as monotherapy compared with chemotherapy. However, the duration of response is limited in the majority of patients treated with BRAF inhibitor monotherapy because of the development of acquired resistance...
January 6, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/28056412/toxicity-of-concurrent-stereotactic-radiotherapy-and-targeted-therapy-or-immunotherapy-a-systematic-review
#12
REVIEW
Stephanie G C Kroeze, Corinna Fritz, Morten Hoyer, Simon S Lo, Umberto Ricardi, Arjun Sahgal, Rolf Stahel, Roger Stupp, Matthias Guckenberger
BACKGROUND AND PURPOSE: Both stereotactic radiotherapy (SRT) and immune- or targeted therapy play an increasingly important role in personalized treatment of metastatic disease. Concurrent application of both therapies is rapidly expanding in daily clinical practice. In this systematic review we summarize severe toxicity observed after concurrent treatment. MATERIAL AND METHODS: PubMed and EMBASE databases were searched for English literature published up to April 2016 using keywords "radiosurgery", "local ablative therapy", "gamma knife" and "stereotactic", combined with "bevacizumab", "cetuximab", "crizotinib", "erlotinib", "gefitinib", "ipilimumab", "lapatinib", "sorafenib", "sunitinib", "trastuzumab", "vemurafenib", "PLX4032", "panitumumab", "nivolumab", "pembrolizumab", "alectinib", "ceritinib", "dabrafenib", "trametinib", "BRAF", "TKI", "MEK", "PD1", "EGFR", "CTLA-4" or "ALK"...
December 19, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28052762/indirect-treatment-comparison-of-dabrafenib-plus-trametinib-versus-vemurafenib-plus-cobimetinib-in-previously-untreated-metastatic-melanoma-patients
#13
Adil Daud, Japinder Gill, Sheily Kamra, Lei Chen, Amit Ahuja
BACKGROUND: Metastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies...
January 4, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28052356/an-overview-of-the-changing-landscape-of-treatment-for-advanced-melanoma
#14
Chung-Shien Lee, Christan M Thomas, Kimberly E Ng
Melanoma-the deadliest form of skin cancer-leads to thousands of deaths each year. Although melanoma is less common than basal cell and squamous cell skin cancers, melanoma is more dangerous because it is more likely to spread to other parts of the body, such as lymph nodes, if not diagnosed and treated early. Data from the National Cancer Institute indicate a steady rise in new cases of melanoma and, unfortunately, a steady rate in the number of deaths through 2013. Ninety percent of melanomas are linked to inadequate sun protection from ultraviolet rays or the tanning habits of young adults...
January 4, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28050146/personalized-oncogenomics-in-the-management-of-gastrointestinal-carcinomas-early-experiences-from-a-pilot-study
#15
B S Sheffield, B Tessier-Cloutier, H Li-Chang, Y Shen, E Pleasance, K Kasaian, Y Li, S J M Jones, H J Lim, D J Renouf, D G Huntsman, S Yip, J Laskin, M Marra, D F Schaeffer
BACKGROUND: Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting. Whole-genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways. METHODS: We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency. Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary, to explore treatment response to bevacizumab in a colorectal cancer, and to characterize an appendiceal adenocarcinoma...
December 2016: Current Oncology
https://www.readbyqxmd.com/read/28002807/concomitant-inhibition-of-receptor-tyrosine-kinases-and-downstream-akt-synergistically-inhibited-growth-of-kras-braf-mutant-colorectal-cancer-cells
#16
Qiaoling Song, Xiaoxiao Sun, Hui Guo, Qiang Yu
Receptor tyrosine kinase (RTK) signaling pathways are frequently activated in cancer cells due to mutations of RTKs and/or their downstream signaling proteins such as KRAS and BRAF. About 40% colorectal cancers (CRCs) contain KRAS or BRAF mutant genes and are resistant to treatments with individual inhibitors of RTKs, AKT, MEK, or BRAF. Therefore, an understanding of the molecular mechanisms of the drug resistance is necessary for developing effective strategies to treat the diseases. Here we report the discovery of an AKT/ERK reactivation mechanism that account for the cancer cell resistance to the AKT and MEK inhibitors treatments...
December 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/28002790/establishment-and-application-of-a-novel-patient-derived-kiaa1549-braf-driven-pediatric-pilocytic-astrocytoma-model-for-preclinical-drug-testing
#17
Florian Selt, Juliane Hohloch, Thomas Hielscher, Felix Sahm, David Capper, Andrey Korshunov, Diren Usta, Sebastian Brabetz, Johannes Ridinger, Jonas Ecker, Ina Oehme, Jan Gronych, Viktoria Marquardt, David Pauck, Heidi Bächli, Charles D Stiles, Andreas von Deimling, Marc Remke, Martin U Schuhmann, Stefan M Pfister, Tilman Brummer, David T W Jones, Olaf Witt, Till Milde
Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor. Activation of the MAPK pathway is well established as the oncogenic driver of the disease. It is most frequently caused by KIAA1549:BRAF fusions, and leads to oncogene induced senescence (OIS). OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures. Hence, valid preclinical models are currently very limited, but preclinical testing of new compounds is urgently needed...
December 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27991907/immunomodulating-property-of-mapk-inhibitors-from-translational-knowledge-to-clinical-implementation
#18
Mario Mandalà, Francesco De Logu, Barbara Merelli, Romina Nassini, Daniela Massi
Treatment of metastatic melanoma was radically changed by the introduction of inhibitors of BRAF, an oncogene mutated in 40-50% of patients. Another area of advancement was the use of immunotherapy, and specifically, immune checkpoint inhibitors. There is compelling evidence that oncogenic BRAF, in addition to driving melanoma proliferation, differentiation and survival, induces T-cell suppression directly through the secretion of inhibitory cytokines or through membrane expression of co-inhibitory molecules such as the PD-1 ligands PD-L1 or PD-L2...
December 19, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/27965097/braf-mutated-cells-activate-gcn2-mediated-integrated-stress-response-as-a-cytoprotective-mechanism-in-response-to-vemurafenib
#19
Ikuko Nagasawa, Kazuhiro Kunimasa, Satomi Tsukahara, Akihiro Tomida
In BRAF-mutated melanoma cells, the BRAF inhibitor, vemurafenib, induces phosphorylation of eukaryotic initiation factor 2α (eIF2α) and subsequent induction of activating transcription factor 4 (ATF4), the central regulation node of the integrated stress response (ISR). While the ISR supports cellular adaptation to various stresses, the role of vemurafenib-triggered ISR has not been fully characterized. Here, we showed that in response to vemurafenib, BRAF-mutated melanoma and colorectal cancer cells rapidly induced the ISR as a cytoprotective mechanism through activation of general control nonderepressible 2 (GCN2), an eIF2α kinase sensing amino acid levels...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27956260/allosteric-mek1-2-inhibitors-including-cobimetanib-and-trametinib-in-the-treatment-of-cutaneous-melanomas
#20
REVIEW
Robert Roskoski
The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer...
December 9, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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