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Johannes Fredebohm, Daniel H Mehnert, Ann-Kathrin Löber, Frank Holtrup, Vanessa van Rahden, Philipp Angenendt, Frank Diehl
We have designed a highly sensitive assay based on the Safe-SeqS technology to detect de novo mutations in the KIT gene and tested its performance. This assay was applied to plasma samples of GIST patients before and after treatment with regorafenib (GRID III trial) and mutations at known and novel sites of potential secondary resistance were identified.
2016: Advances in Experimental Medicine and Biology
Hao-Wei Teng, Man-Hsin Hung, Li-Ju Chen, Mao-Ju Chang, Feng-Shu Hsieh, Ming-Hsien Tsai, Jui-Wen Huang, Chih-Lung Lin, Hsiang-Wen Tseng, Zong-Keng Kuo, Jeng-Kai Jiang, Shung-Haur Yang, Chung-Wai Shiau, Kuen-Feng Chen
Protein tyrosine phosphatase 1B (PTP1B) is known to promote the pathogenesis of diabetes and obesity by negatively regulating insulin and leptin pathways, but its role associated with colon carcinogenesis is still under debate. In this study, we demonstrated the oncogenic role of PTP1B in promoting colon carcinogenesis and predicting worse clinical outcomes in CRC patients. By co-immunoprecipitation, we showed that PITX1 was a novel substrate of PTP1B. Through direct dephosphorylation at Y160, Y175 and Y179, PTP1B destabilized PITX1, which resulted in downregulation of the PITX1/p120RasGAP axis...
October 18, 2016: Scientific Reports
John H Healey
No abstract text is available yet for this article.
October 14, 2016: Lancet Oncology
Olivier Mir, Thomas Brodowicz, Antoine Italiano, Jennifer Wallet, Jean-Yves Blay, François Bertucci, Christine Chevreau, Sophie Piperno-Neumann, Emmanuelle Bompas, Sébastien Salas, Christophe Perrin, Corinne Delcambre, Bernadette Liegl-Atzwanger, Maud Toulmonde, Sarah Dumont, Isabelle Ray-Coquard, Stéphanie Clisant, Sophie Taieb, Cécile Guillemet, Maria Rios, Olivier Collard, Laurence Bozec, Didier Cupissol, Esma Saada-Bouzid, Christine Lemaignan, Wolfgang Eisterer, Nicolas Isambert, Loïc Chaigneau, Axel Le Cesne, Nicolas Penel
BACKGROUND: Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. METHODS: In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment...
October 14, 2016: Lancet Oncology
Masatoshi Kudo
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer deaths worldwide. Sonazoid-enhanced ultrasound and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced MRI are the most important imaging modalities in diagnosing HCC. There are 2 non-contradictory HCC treatment algorithms in Japan. Hepatic arterial infusion chemotherapy plays an important role in the treatment of advanced HCC with main or branch portal vein invasion. Regorafenib, as a second-line systemic treatment, prolongs survival in patients with intermediate and advanced HCC who progressed on sorafenib...
2016: Digestive Diseases
Dieter Zopf, Iduna Fichtner, Ajay Bhargava, Wolfram Steinke, Karl-Heinz Thierauch, Konstanze Diefenbach, Scott Wilhelm, Frank-Thorsten Hafner, Michael Gerisch
Regorafenib is an orally administered inhibitor of protein kinases involved in tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment. Phase III studies showed that regorafenib has efficacy in patients with advanced gastrointestinal stromal tumors or treatment-refractory metastatic colorectal cancer. In clinical studies, steady-state exposure to the M-2 and M-5 metabolites of regorafenib was similar to that of the parent drug; however, the contribution of these metabolites to the overall observed clinical activity of regorafenib cannot be investigated in clinical trials...
October 13, 2016: Cancer Medicine
Jörg Trojan, Oliver Waidmann
Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016...
2016: J Hepatocell Carcinoma
S M Dieter, C Heining, A Agaimy, D Huebschmann, D Bonekamp, B Hutter, K R Ehrenberg, M Fröhlich, M Schlesner, C Scholl, H-P Schlemmer, S Wolf, A Mavratzas, C S Jung, S Gröschel, C V Kalle, R Eils, B Brors, R Penzel, M Kriegsmann, D E Reuss, P Schirmacher, A Stenzinger, P A Federspil, W Weichert, H Glimm, S Fröhling
BACKGROUND: Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Yoshihito Ohhara, Naoki Fukuda, Satoshi Takeuchi, Rio Honma, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita
Colorectal cancer (CRC) is a significant cause of cancer-related morbidity and mortality all over the world. Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC (mCRC), with a median overall survival of approximately 2 years and more in the past two decades. The biologic agents that have proven clinical benefits in mCRC mainly target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In particular, bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated significant survival benefits in combination with cytotoxic chemotherapy in the first-line, second-line, or salvage setting...
September 15, 2016: World Journal of Gastrointestinal Oncology
Toshiki Masuishi, Hiroya Taniguchi, Satoshi Hamauchi, Azusa Komori, Yosuke Kito, Yukiya Narita, Takahiro Tsushima, Makoto Ishihara, Akiko Todaka, Tsutomu Tanaka, Tomoya Yokota, Shigenori Kadowaki, Nozomu Machida, Takashi Ura, Akira Fukutomi, Masashi Ando, Yusuke Onozawa, Masahiro Tajika, Hirofumi Yasui, Kei Muro, Keita Mori, Kentaro Yamazaki
BACKGROUND: Regorafenib and trifluridine/tipiracil (TAS-102) both prolong survival for patients with refractory metastatic colorectal cancer. However, it is unclear which drug should be administered first. MATERIALS AND METHODS: We retrospectively evaluated the data from patients who had received regorafenib or TAS-102 at 2 institutions from May 2013 to March 2015. The inclusion criteria were disease refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor antibodies, and anti-epidermal growth factor receptor (EGFR) antibodies (if KRAS exon 2 wild-type), and no previous treatment with regorafenib or TAS-102...
August 31, 2016: Clinical Colorectal Cancer
Florence T H Wu, Shan Man, Ping Xu, Annabelle Chow, Marta Paez-Ribes, Christina R Lee, Steven R Pirie-Shepherd, Urban Emmenegger, Robert S Kerbel
Antiangiogenic tyrosine kinase inhibitors (TKIs) that target VEGF receptor-2 (VEGFR2) have not been effective as adjuvant treatments for micrometastatic disease in phase III trials. Angiopoietin-2 (Ang2) is a pro-angiogenic and pro-inflammatory vascular destabilizer that cooperates with VEGF. The purpose of this study was to test whether CVX-060 (an Ang2-specific CovX-body) can be combined with VEGFR2-targeting TKIs (sunitinib or regorafenib) to successfully treat postsurgical metastatic disease in multiple orthotopically implanted human tumor xenograft and syngeneic murine tumor models...
September 20, 2016: Cancer Research
Katerina Kopeckova, Tomas Buchler, Zbynek Bortlicek, Karel Hejduk, Renata Chloupkova, Bohuslav Melichar, Petra Pokorna, Jiri Tomasek, Zdenek Linke, Lubos Petruzelka, Igor Kiss, Jana Prausova
OBJECTIVE: To describe the use of regorafenib for the treatment of metastatic colorectal cancer (mCRC) in clinical practice in the Czech Republic, and to describe the clinical outcomes of patients in terms of safety and survival. PATIENTS AND METHODS: The data of patients treated with regorafenib were extracted from the national CORECT registry. The CORECT registry is a non-interventional post-marketing database, gathering information about patients with CRC and treated with targeted agents...
September 14, 2016: Targeted Oncology
Ramya Chockalingam, Phyu Aung, Anisha B Patel
Regorafenib is a second-generation multikinase inhibitor that is approved for the treatment of metastatic colon cancer and advanced gastrointestinal stromal tumors. Hand-foot skin reaction, alopecia, and oral mucositis are well-established side effects of this medication. Herein, we discuss a 60-year-old woman who developed a lobular and septal granulomatous panniculitis after six months of therapy with regorafenib. Biopsy demonstrated focal lobular and septal granulomatous inflammation admixed with septal fibrosis and lobular lymphohistiocytic infiltrate associated with fat necrosis...
2016: Dermatology Online Journal
Andrea Ribeiro de Souza, Maria Reig, Jordi Bruix
INTRODUCTION: Hepatocelullar carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite the implementation of screening programs for high-risk individuals, a significant proportion of patients present with advanced disease at the moment of diagnosis. AREAS COVERED: In this review we will focus in the current treatment of advanced HCC, the research that has been done in the past few years, the achievements and failures in this setting and future perspectives...
October 2016: Expert Opinion on Pharmacotherapy
Ivan Haralampiev, Holger A Scheidt, Tobias Abel, Madlen Luckner, Andreas Herrmann, Daniel Huster, Peter Müller
Sorafenib and regorafenib are small-molecule kinase inhibitors approved for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma, renal cell carcinoma, and hepatocellular carcinoma (sorafenib) and of colorectal cancer (regorafenib). As of now, the mechanisms, which are responsible for their antitumor activities, are not completely understood. Given the lipophilic nature of the molecules, it can be hypothesized that the pharmacological impact is mediated by the interaction with cellular membranes as it is true for many pharmacologically active molecules...
August 28, 2016: Biochimica et Biophysica Acta
Li-Ching Fan, Hao-Wei Teng, Chung-Wai Shiau, Wei-Tien Tai, Man-Hsin Hung, Shung-Haur Yang, Jeng-Kai Jiang, Kuen-Feng Chen
Epithelial-to-mesenchymal transition (EMT) is well-known to evoke cancer invasion/metastasis, leading to a high frequency of mortality in patients with metastatic colorectal cancer (mCRC). Protein tyrosine phosphatase (PTPase)-targeted therapy has been identified as a novel cancer therapeutic. Previously, we proved that sorafenib with anti-EMT potency prevents TGF-β1-induced EMT/invasion by directly activating SH2-domain-containing phosphatase 1 (SHP-1)-dependent p-STAT3Tyr705 suppression in hepatocellular carcinoma...
August 26, 2016: Oncotarget
Riccardo Giampieri, Angelo Restivo, Valeria Pusceddu, Michela Del Prete, Elena Maccaroni, Alessandro Bittoni, Luca Faloppi, Kalliopi Andrikou, Maristella Bianconi, Francesco Cabras, Rossana Berardi, Luigi Zorcolo, Francesco Scintu, Stefano Cascinu, Mario Scartozzi
BACKGROUND: The potential clinical impact of aspirin use beyond its canonical indications is a novel matter of scientific debate. In patients with metastatic colorectal cancer failing all available options, regorafenib and TAS 102 represent the only chance of treatment. Although effective, these therapeutic options bring along a not-negligible burden in terms of economic costs and toxicity. In this setting, the indication to use aspirin in combination with chemotherapy would potentially represent a medical revolution under the economic and toxicity profile...
August 4, 2016: Clinical Colorectal Cancer
Felice Pasini, Anna Paola Fraccon, Yasmina Modena, Maria Bencivenga, Simone Giacopuzzi, Francesca La Russa, Milena Gusella, Giovanni de Manzoni
Despite improvements in systemic chemotherapy (CT), the prognosis of metastatic adenocarcinoma of the gastroesophageal junction remains poor. Over the years, new targeting agents have become available and were tested, with or without CT, in first or subsequent lines of therapy. The epidermal growth factor receptor family was targeted with monoclonal antibodies (MoAbs) (trastuzumab, cetuximab, panitumumab) and tyrosin kinase inhibitors (TKIs) (lapatinib, erlotinib, gefitinib). Only trastuzumab, in combination with cisplatin and fluoropyrimidines, significantly improved overall survival (OS) in first-line therapy (13...
August 27, 2016: Gastric Cancer
Anant Ramaswamy, Nikhil Pande, Omshree Shetty, Nitin Shetty, Sudeep Gupta, Vikas Ostwal
BACKGROUND: A median progression free survival (PFS) of 18-20 months and median overall survival (OS) of 51-57 months can be achieved with the use of imatinib, in metastatic or advanced gastrointestinal stromal tumor (GIST). Sunitinib and regorafenib are approved options for patients progressing on imatinib, but with markedly decreased survival. pazopanib is a broad spectrum TKI targeting KIT, PDGFR and VEGFR receptors and has shown promising activity in phase 2 trials in GIST. METHODS: All patients who received pazopanib for GIST between March 2014 and September 2015 in our institution were reviewed...
August 2016: Journal of Gastrointestinal Oncology
Kristen K Ciombor, Richard M Goldberg
Angiogenesis is a complex biologic process critical to growth and proliferation of colorectal cancer. The safety and efficacy of various anti-angiogenic agents have been investigated in many treatment settings. Bevacizumab, an anti-vascular endothelial growth factor agent, has efficacy in both the first-line setting and beyond progression in metastatic colorectal cancer. The decoy vascular endothelial growth factor receptor aflibercept has been approved in combination with 5-fluorouracil, leucovorin and irinotecan-based chemotherapy in metastatic colorectal cancer patients whose disease has progressed on a prior oxaliplatin-based chemotherapy regimen...
December 2015: Current Colorectal Cancer Reports
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