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Lea Bottlaender, Marie Perier-Muzet, Véronique Lapras, Luc Thomas, Stephane Dalle
BRAF inhibitors (vemurafenib and dabrafenib) are nowadays commonly prescribed in BRAF-mutant metastatic melanoma and allow improvement of the overall survival and progression-free survival. They are, however, accompanied by many adverse effects which mainly affect the skin. We observed on computed tomographic scans in three different patients after 3 months of treatment, the onset of osteosclerotic lesions. In parallel, the computed tomographic scans showed a significant reduction in all of the previously identified metastases in all patients...
October 18, 2016: Melanoma Research
Kento Kurata, Naoyoshi Onoda, Satoru Noda, Shinichiro Kashiwagi, Yuka Asano, Kosei Hirakawa, Masaichi Ohira
Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated...
October 7, 2016: International Journal of Oncology
Stefan Grossauer, Katharina Koeck, Nicole E Murphy, Ian D Meyers, Mathieu Daynac, Nathalene Truffaux, Albert Y Truong, Theodore P Nicolaides, Martin McMahon, Mitchel S Berger, Joanna J Phillips, C David James, Claudia K Petritsch
Inhibitors of BRAFV600E kinase are currently under investigations in preclinical and clinical studies involving BRAFV600E glioma. Studies demonstrated clinical response to such individualized therapy in the majority of patients whereas in some patients tumors continue to grow despite treatment. To study resistance mechanisms, which include feedback activation of mitogen-activated protein kinase (MAPK) signaling in melanoma, we developed a luciferase-modified cell line (2341luc) from a BrafV600E mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAFV600E- and MAPK kinase (MEK)-targeted inhibition...
October 3, 2016: Oncotarget
Ana Cebollero, Teresa Puértolas, Isabel Pajares, Lourdes Calera, Antonio Antón
A retrospective observational study was conducted on patients diagnosed with serine/threonine-protein kinase B-Raf (BRAF)-mutated metastatic melanoma, who underwent first-line therapy with BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors (vemurafenib, dabrafenib or a combination of dabrafenib and trametinib) at the Miguel Servet University Hospital (Zaragoza, Spain) between November, 2011 and August, 2015. The aim of this study was to analyse the toxicity produced by BRAF and MEK inhibitors...
October 2016: Molecular and Clinical Oncology
Rishi Agarwal, Jiang Wang, Keith Wilson, William Barrett, John C Morris
Anaplastic thyroid cancer (ATC) is an aggressive uncommon malignancy with limited treatment. Traditional antineoplastic chemotherapy has not been successful in the management of metastatic ATC. As a result, the focus has shifted to the development of novel therapies for this disease. The availability of economical comprehensive genomic profiling (CGP) platforms with rapid turn-around to identify molecular aberrations in tumors that are potential therapeutic targets has increasingly changed the face of cancer therapy...
October 2016: Journal of the National Comprehensive Cancer Network: JNCCN
S Pinar Bilir, Qiufei Ma, Zhongyun Zhao, Elizabeth Wehler, Julie Munakata, Beth Barber
BACKGROUND: Little has been reported on the costs of managing the adverse events (AEs) associated with current therapies for patients with regional or distant metastatic melanoma. OBJECTIVES: To identify treatment-related AEs in patients with metastatic melanoma and to estimate the associated costs of treating these AEs in the United States. METHODS: A cost-estimation study for AEs associated with treatment of metastatic melanoma was conducted from 2012 to 2013 by identifying grades 3 and 4 AEs through the use of a comprehensive search of drug labels and English-language, published phase 2/3 studies in PubMed, conference abstracts, and the National Comprehensive Cancer Network guidelines...
June 2016: American Health & Drug Benefits
Emily de Golian, Bernice Y Kwong, Susan M Swetter, Silvina B Pugliese
The landscape of advanced and metastatic melanoma therapy has shifted dramatically in recent years. Since 2011, eight drugs (ipilimumab, vemurafenib, dabrafenib, trametinib, cometinib, pembrolizumab, nivolumab, and talimogene laherparepvec) have received FDA approval for the treatment of advanced or metastatic melanoma, including combination regimens of both small molecule kinase and immune checkpoint inhibitors. These therapies have revolutionized the management of unresectable regional nodal and distant melanoma, providing hope of extended survival to patients...
November 2016: Current Treatment Options in Oncology
Jean-Philip Lacroix, Beatrice Wang
BACKGROUND: Dabrafenib, a novel selective small-molecule inhibitor of BRAF, has been shown to increase overall survival in patients with unresectable metastatic melanoma harboring the BRAF V600E mutation. The development of resistance has led to combination therapy with selective MEK inhibitor trametinib. Compared with vemurafenib, dabrafenib is a more recent BRAF inhibitor approved by the Food and Drug Administration in May 2013 for metastatic melanoma; fewer data are available in the current literature regarding cutaneous toxicity...
September 13, 2016: Journal of Cutaneous Medicine and Surgery
Blanca Homet Moreno, Stephen Mok, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma...
July 2016: Oncoimmunology
Lorenzo Gerratana, Giovanna De Maglio, Alessandro De Pellegrin, Alessandro Follador, Karim Rihawi, Stefano Pizzolitto, Fabio Puglisi, Gianpiero Fasola
Molecular characterization is increasingly changing clinical practice, in both diagnosis and treatment. BRAF is a proto-oncogene that is mutated in ~2%-4% of lung cancers, but the incidence rises to 40%-45% among papillary thyroid cancers. Furthermore, BRAF is a promising target in lung cancer treatment. The present case study covers both the challenges of molecular differential diagnosis and the perspectives opened by targeted therapy by discussing the history of a 78-year-old female affected by a papillary histotype carcinoma with BRAF mutation associated with both thyroid and lung localizations...
2016: OncoTargets and Therapy
Alfredo Agulló, Brian Hinds, Raquel Santesteban, Josune Mitxelena Mitxelena, Ignacio Yanguas
Agminated melanocytic nevus is an uncommon type of mole, characterized by a local group of macular or papular pigmented lesions, well demarcated, without a common pigmented background. This pattern has also been associated with Spitz nevi, dysplastic melanocytic nevi, and non-melanocytic lesions.We describe the onset of an acquired agminated melanocytic nevus after dabrafenib treatment. Our case highlights paradoxical MAPK activation in the setting of single-agent BRAF blockade and underscores the importance of characterizing the diverse side effects of selective BRAF inhibitors...
2016: Dermatology Online Journal
Kevin Wood, Jason J Luke
PURPOSE OF REVIEW: The therapeutic landscape for metastatic melanoma has been revolutionized in recent years. This review will discuss existing evidence for therapeutic approaches for BRAF-mutated metastatic melanoma. RECENT FINDINGS: Clinical trials involving combined BRAF/MEK inhibition with either vemurafenib plus cobimetinib or dabrafenib plus trametinib have shown improved overall survival compared to monotherapy with BRAF inhibitors alone. In a subset of patients with good prognostic factors, long-term clinical benefit has been noted...
November 2016: Current Oncology Reports
Marta Troya-Castilla, Santiago Rocha-Romero, Yamin Chocrón-González, Francisco Javier Márquez-Rivas
BACKGROUND: Primary brain melanomas are very infrequent and metastasis outside central nervous system very uncommon. There are some cases in the literature about primary melanoma in the temporal lobe; nevertheless, the insular location has never been described. CASE PRESENTATION: The patient presented as left insular intraparenchymal hematoma with multiple bleedings. Complementary tests did not show any tumoral nor vascular pattern in relation with these bleedings...
2016: World Journal of Surgical Oncology
Amir Noeparast, Erik Teugels, Philippe Giron, Gil Verschelden, Sylvia De Brakeleer, Lore Decoster, Jacques De Grève
Approximately half of BRAF-mutated Non-small cell lung cancers (NSCLCs) harbor a non-V600 BRAF mutation, accounting for ~40,000 annual deaths worldwide. Recent studies have revealed the benefits of combined targeted therapy with a RAF-inhibitor (Dabrafenib) and a MEK-inhibitor (Trametinib) in treating V600 BRAF mutant cancers, including NSCLC. In contrast, sensitivity of non-V600 BRAF mutations to these inhibitors is not documented. Non-V600 mutations can either increase or impair BRAF kinase activity. However, impaired BRAF kinases can still activate the ERK pathway in a CRAF-dependent manner...
August 26, 2016: Oncotarget
Kateřina Vlčková, Jiri Réda, Lubica Ondrušová, Mohammad Krayem, Ghanem Ghanem, Jiri Vachtenheim
MEK kinase inhibitors (trametinib and selumetinib) or kinase inhibitors directed against mutated BRAF(V600E) (vemurafenib and dabrafenib) have initial encouraging effects in the treatment of melanoma but acquired resistance appears almost invariably after some months. Studies revealed mutually exclusive NRAS and BRAF activating mutations driving the MAPK/ERK pathway among human melanomas. Although combination therapy exerts significantly better antitumor cell efficacy, complete remission is rarely achieved...
September 2016: International Journal of Oncology
Simona Caporali, Ester Alvino, Pedro Miguel Lacal, Lauretta Levati, Giorgio Giurato, Domenico Memoli, Elisabetta Caprini, Gian Carlo Antonini Cappellini, Stefania D'Atri
BRAF inhibitors (BRAFi) have proven clinical benefits in patients with BRAF-mutant melanoma. However, acquired resistance eventually arises. The effects of BRAFi on melanoma cell proliferation and survival have been extensively studied, and several mechanisms involved in acquired resistance to the growth suppressive activity of these drugs have been identified. Much less is known about the impact of BRAFi, and in particular of dabrafenib, on the invasive potential of melanoma cells. In the present study, the BRAF-mutant human melanoma cell line A375 and its dabrafenib-resistant subline A375R were analyzed for invasive capacity, expression of vascular endothelial growth factor receptor (VEGFR)-2, and secretion of VEGF-A and matrix metalloproteinase (MMP)-9, under basal conditions or in response to dabrafenib...
September 2016: International Journal of Oncology
Ivar S Jensen, Emily Zacherle, Christopher M Blanchette, Jie Zhang, Wes Yin
BACKGROUND: Although a number of monoimmunotherapies and targeted therapies are available to treat BRAF+ advanced melanoma, response rates remain relatively low in the range of 22-53% with progression-free survival (PFS) in the range of 4.8-8.8 months. Recently, combination targeted therapies have improved response rates to about 66-69%, PFS to 11.0-12.6 months and overall survival (OS) to 25.1-25.6 months. While combination immunotherapies have improved response rates of 67 compared with 19-29% with monotherapies and improved PFS of 11...
2016: Drugs in Context
Chao Ji, Ziping Zhang, Lihong Chen, Kunli Zhou, Dongjun Li, Ping Wang, Shuying Huang, Ting Gong, Bo Cheng
Melanoma is one of the deadliest skin cancers and accounts for most skin-related deaths due to strong resistance to chemotherapy drugs. In the present study, we investigated the mechanisms of dabrafenib-induced drug resistance in human melanoma cell lines A375 and MEL624. Our studies support that both endoplasmic reticulum (ER) stress and autophagy were induced in the melanoma cells after the treatment with dabrafenib. In addition, ER stress-induced autophagy protects melanoma cells from the toxicity of dabrafenib...
2016: Drug Design, Development and Therapy
Thomas E Stinchcombe
Targeted therapies have become standard therapies for patients with non-small cell lung cancer (NSCLC). A phase III trial of carboplatin and paclitaxel with and without bevacizumab in patients with advanced NSCLC with non-squamous histology demonstrated a statistically significant improvement in efficacy. In patients with NSCLC with an activating epidermal growth factor receptor (EGFR) mutation (defined as exon 19 deletion and exon 21 L858R point mutation), phase III trials of EGFR tyrosine kinase inhibitors (TKI) compared to platinum-based chemotherapy have demonstrated superior efficacy in the first-line setting...
2016: Cancer Treatment and Research
Stefano Cavalieri, Lorenza Di Guardo, Carolina Cimminiello, Aldo Bono, Elena Tolomio, Anna Colombetti, Barbara Valeri, Giuseppe Di Tolla, Filippo de Braud, Michele Del Vecchio
PURPOSE: Combination therapy with dabrafenib and trametinib is safer and more effective than BRAF inhibitor-based monotherapy for metastatic melanoma. METHODS: We retrospectively analyzed BRAF-mutated metastatic melanoma patients treated at our institution with daily oral dabrafenib 300 mg and trametinib 2 mg from November 2013 to April 2016. This clinical record included both untreated and previously treated stage IV melanomas. Physical examination and laboratory examinations were performed monthly and disease re-evaluations were performed every 3 months...
October 13, 2016: Tumori
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