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tyrosine kinase inhibitor

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https://www.readbyqxmd.com/read/29241084/neoadjuvant-radiotherapy-combined-with-capecitabine-and-sorafenib-in-patients-with-advanced-kras-mutated-rectal-cancer-a-phase-i-ii-trial-sakk-41-08
#1
Roger von Moos, Dieter Koeberle, Sabina Schacher, Stefanie Hayoz, Ralph C Winterhalder, Arnaud Roth, György Bodoky, Panagiotis Samaras, Martin D Berger, Daniel Rauch, Piercarlo Saletti, Ludwig Plasswilm, Daniel Zwahlen, Urs R Meier, Pu Yan, Paola Izzo, Dirk Klingbiel, Daniela Bärtschi, Kathrin Zaugg
BACKGROUND: KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety...
December 11, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29240787/brd3-4-inhibition-and-flt3-ligand-deprivation-target-pathways-that-are-essential-for-the-survival-of-human-mll-af9-leukemic-cells
#2
Marco Carretta, Annet Z Brouwers-Vos, Matthieu Bosman, Sarah J Horton, Joost H A Martens, Edo Vellenga, Jan Jacob Schuringa
In the present work we aimed to identify targetable signaling networks in human MLL-AF9 leukemias. We show that MLL-AF9 cells critically depend on FLT3-ligand induced pathways as well as on BRD3/4 for their survival. We evaluated the in vitro and in vivo efficacy of the BRD3/4 inhibitor I-BET151 in various human MLL-AF9 (primary) models and patient samples and analyzed the transcriptome changes following treatment. To further understand the mode of action of BRD3/4 inhibition, we performed ChIP-seq experiments on the MLL-AF9 complex in THP1 cells and compared it to RNA-seq data of I-BET151 treated cells...
2017: PloS One
https://www.readbyqxmd.com/read/29239838/mediator-kinase-phosphorylation-of-stat1-s727-promotes-growth-of-neoplasms-with-jak-stat-activation
#3
Ioana I Nitulescu, Sara C Meyer, Qiang Jeremy Wen, John D Crispino, Madeleine E Lemieux, Ross L Levine, Henry E Pelish, Matthew D Shair
Constitutive JAK-STAT signaling drives the proliferation of most myeloproliferative neoplasms (MPN) and a subset of acute myeloid leukemia (AML), but persistence emerges with chronic exposure to JAK inhibitors. MPN and post-MPN AML are dependent on tyrosine phosphorylation of STATs, but the role of serine STAT1 phosphorylation remains unclear. We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727...
November 21, 2017: EBioMedicine
https://www.readbyqxmd.com/read/29239327/influence-of-vascular-endothelial-growth-factor-and-radiation-on-gap-junctional-intercellular-communication-in-glioblastoma-multiforme-cell-lines
#4
Reinhardt Krcek, Pauline Latzer, Irenäus Anton Adamietz, Helmut Bühler, Carsten Theiss
Glioblastoma multiforme (GBM) is a highly aggressive glial brain tumor with an unfavorable prognosis despite all current therapies including surgery, radiation and chemotherapy. One characteristic of this tumor is a strong synthesis of vascular endothelial growth factor (VEGF), an angiogenesis factor, followed by pronounced vascularization. VEGF became a target in the treatment of GBM, for example with bevacizumab or the tyrosine kinase inhibitor axitinib, which blocks VEGF receptors. To improve patients' prognosis, new targets in the treatment of GBM are under investigations...
November 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/29239193/-checkpoint-inhibitors-in-the-treatment-of-upper-gastrointestinal-tract-tumors
#5
R Obermannova
Chemotherapy prolongs overall survival (OS) in esophageal (EC) and gastric cancer (GC). Unsatisfactory results of systemic therapy initiated a search for new treatment options. In metastatic disease, a number of targeted drugs were tested; however, several phase III studies assessing receptor tyrosin kinase-related signaling pathways, such as EGFR, MET/HGF or mTOR, failed. Trastuzumab remains the only targeted drug with a known molecular predictor, which extended the OS in metastatic gastric adenocarcinoma and adenocarcinoma of esophago-gastric junction...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/29239110/association-of-prognostic-features-and-treatment-on-survival-time-of-dogs-with-systemic-mastocytosis-a-retrospective-analysis-of-40-dogs
#6
S J Moirano, S F Lima, K R Hume, E M Brodsky
Systemic mastocytosis is a rare phenomenon, with limited information regarding prognostic features and effective treatment of canine patients with this disease. The objective of this study is to determine the impact of certain features and treatments on dogs with systemic mastocytosis. The medical records of 40 dogs from 4 northeastern US veterinary hospitals, with evidence of systemic mast cell disease, were evaluated retrospectively. Variables analysed with relation to overall survival and prognostic significance included treatment protocol used, substage, presence of a cutaneous or visceral tumour, presence of multiple cutaneous Mast cell tumours, grade of the primary tumour and metastatic site(s)...
December 14, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/29239002/pharmacokinetics-of-osimertinib-in-chinese-patients-with-advanced-nsclc-a-phase-1-study
#7
Hongyun Zhao, Junning Cao, Jianhua Chang, Zhenxian Zhang, Li Yang, Jia Wang, Mireille Cantarini, Li Zhang
Osimertinib is an oral, irreversible, central nervous system active epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing and T790M resistance mutations. The study's (NCT02529995) primary objective was to characterize the pharmacokinetics (PK) of osimertinib and its metabolites in Chinese patients enrolled in China. PK was assessed following single and multiple doses of 40 or 80 mg osimertinib once daily. Patients were aged ≥ 18 years with locally advanced or metastatic EGFR-TKI-sensitizing (EGFRm) non-small cell lung cancer and World Health Organization performance status of 0/1, who had progressed following prior EGFR-TKI...
December 14, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29238707/drug-repurposing-for-the-treatment-of-acute-myeloid-leukemia
#8
REVIEW
Vibeke Andresen, Bjørn T Gjertsen
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of immature myeloid progenitor cells in the bone marrow, compromising of normal blood cell production and ultimately resulting in bone marrow failure. With a 20% overall survival rate at 5 years and 50% in the 18- to 65-year-old age group, new medicines are needed. It is proposed that development of repurposed drugs may be a part of the new therapy needed. AML is subdivided into recurrent molecular entities based on molecular genetics increasingly accessible for precision medicine...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/29238696/identification-of-clinically-approved-drugs-indacaterol-and-canagliflozin-for-repurposing-to-treat-epidermal-growth-factor-tyrosine-kinase-inhibitor-resistant-lung-cancer
#9
Hongjian Li, Christy Wing-Sum Tong, Yee Leung, Man-Hon Wong, Kenneth Kin-Wah To, Kwong-Sak Leung
In advanced lung cancer, epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) have extraordinary clinical efficacy. However, their usefulness is severely compromised by drug resistance mediated by various mechanisms, the most important of which is the secondary EGFR T790M mutation. The mutation blocks the binding of EGFR TKIs to the receptor kinase, thereby abolishing the therapeutic efficacy. In this study, we used our free and open-source protein-ligand docking software idock to screen worldwide approved small-molecule drugs against EGFR T790M...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/29237806/afatinib-is-a-new-therapeutic-approach-in-chordoma-with-a-unique-ability-to-target-egfr-and-brachyury
#10
Paola Magnaghi, Barbara Salom, Liviana Cozzi, Nadia Amboldi, Dario Ballinari, Elena Tamborini, Fabio Gasparri, Alessia Montagnoli, Laura Raddrizzani, Alessio Somaschini, Roberta Bosotti, Christian Orrenius, Fabio Bozzi, Silvana Pilotti, Arturo Galvani, Josh Sommer, Silvia Stacchiotti, Antonella Isacchi
Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in Phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRβ and EGFR tyrosine kinases, and assessed their anti-proliferative activity against a panel of chordoma cell lines...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29237805/preclinical-evaluation-of-scc244-glumetinib-a-novel-potent-and-highly-selective-inhibitor-of-c-met-in-met-dependent-cancer-models
#11
Jing Ai, Yi Chen, Xia Peng, Yinchun Ji, Yong Xi, Yanyan Shen, Xinying Yang, Yi Su, Yi-Ming Sun, Yinglei Gao, Yuchi Ma, Bing Xiong, Jingkang Shen, Jian Ding, Meiyu Geng
Because the receptor tyrosine kinase c-Met plays a critical role in tumor growth, metastasis, tumor angiogenesis and drug resistance, the c-Met axis represents an attractive therapeutic target. Herein, we report the first preclinical characterization of SCC244, a novel, potent and highly selective inhibitor of c-Met kinase. SCC244 showed subnanomolar potency against c-Met kinase activity and high selectivity versus 312 other tested protein kinases, making it one of the most selective c-Met inhibitors described to date...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29237803/anti-tumor-activity-of-entrectinib-a-pan-trk-ros1-and-alk-inhibitor-in-etv6-ntrk3-positive-acute-myeloid-leukemia
#12
Kristen M Smith, Patrick C Fagan, Elena Pomari, Giuseppe Germano, Chiara Frasson, Colin Walsh, Ian M Silverman, Paolo Bonvini, Gang Li
Activation of tropomyosin receptor kinase (TRK) family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent and selective kinase inhibitor against TRKA/B/C, ROS1 and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion-driven hematologic malignancies...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29237484/the-clinical-efficacy-of-afatinib-30%C3%A2-mg-daily-as-starting-dose-may-not-be-inferior-to-afatinib-40%C3%A2-mg-daily-in-patients-with-stage-iv-lung-adenocarcinoma-harboring-exon-19-or-exon-21-mutations
#13
Chih-Jen Yang, Ming-Ju Tsai, Jen-Yu Hung, Mei-Hsuan Lee, Ying-Ming Tsai, Yu-Chen Tsai, Jui-Feng Hsu, Ta-Chih Liu, Ming-Shyan Huang, Inn-Wen Chong
BACKGROUND: Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Compared to cytotoxic chemotherapy, afatinib has been shown to have better efficacy in the treatment of non-small cell lung cancer harboring EGFR mutations. However, 40 mg daily as the initial dose is often accompanied by serious adverse drug reactions (ADRs) and 28 to 53.3% of patients required a dose reduction. No previous study has compared the clinical efficacy and ADRs of different initial doses (40 mg vs...
December 13, 2017: BMC Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29237381/targeting-fgfr-with-bgj398-in-breast-cancer-effect-on-tumor-growth-and-metastasis
#14
Ana Sahores, Maria May, Gonzalo Sequeira, Cynthia Fuentes, Britta Jacobsen, Claudia Lanari, Caroline Ana Lamb
BACKGROUND: Endocrine resistance and metastatic dissemination comprise major clinical challenges for breast cancer treatment. The fibroblast growth factor receptor family (FGFR) consists of four tyrosine kinase transmembrane receptors, involved in key biological processes. Genomic alterations in FGFR have been identified in advanced breast cancer and thus, FGFR are an attractive therapeutic target. However, the efficacy of FGFR inhibitors on in vivo tumor growth is still controversial...
December 13, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/29237346/arachidonic-acid-reverses-xanthohumol-induced-insufficiency-in-a-human-first-trimester-extravillous-trophoblast-cell-line-htr-8-svneo-cells
#15
Ana Correia-Branco, Elisa Keating, Fátima Martel
We previously described a negative effect of xanthohumol (XN) upon placentation-related processes. We aimed to better characterize this effect by investigating the effect of XN upon the uptake of arachidonic acid (ARA), a crucial nutrient during pregnancy, by the HTR-8/SVneo human first-trimester extravillous trophoblast cell line and its relationship with the negative effect of XN upon placentation-related processes. Uptake of 14C-ARA (100 nM) was time dependent and inhibited by short-term (26 minutes) or long-term (24 hours) exposure to XN...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/29236617/how-does-one-decide-which-tyrosine-kinase-inhibitor-to-use-for-the-initial-treatment-of-chronic-phase-chronic-myeloid-leukemia
#16
Kenneth R Hoffman
No abstract text is available yet for this article.
February 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29235562/targeting-the-raf-kinases-in-human-cancer-the-raf-dimer-dilemma
#17
David E Durrant, Deborah K Morrison
The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alterations in upstream Raf regulators, including Ras and receptor tyrosine kinases. First-generation Raf inhibitors, such as vemurafenib and dabrafenib, have yielded dramatic responses in malignant melanomas containing B-Raf mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance...
December 12, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29234489/molecular-insights-suppression-of-egfr-and-akt-activation-by-a-small-molecule-in-non-small-cell-lung-cancer
#18
Balaji Chandrasekaran, Ashish Tyagi, Arun K Sharma, Lu Cai, Murali Ankem, Chendil Damodaran
Epidermal growth factor receptor (EGFR) activation events and the mammalian target of rampamycin (mTOR) are considered important therapeutic targets in alleviating cancer conditions. The current treatment paradigm has shifted to personalized treatment strategies with tyrosine kinase inhibitors (TKIs) or anaplastic lymphoma kinase (ALK) inhibitors, due to low survival rates in non-small cell lung cancer (NSCLC) in terms of the prevailing platinum-based therapy. In the present study, we examined the anticancer potential of Verrucarin J (VJ), a small molecule, in NSCLC cell lines (H460 and A549)...
September 2017: Genes & Cancer
https://www.readbyqxmd.com/read/29233926/targeting-cdk6-and-bcl2-exploits-the-myb-addiction-of-ph-acute-lymphoblastic-leukemia
#19
Marco De Dominici, Patrizia Porazzi, Angela Rachele Soliera, Samanta A Mariani, Sankar Addya, Paolo Fortina, Luke F Peterson, Orietta Spinelli, Alessandro Rambaldi, Giovanni Martinelli, Anna Ferrari, Ilaria Iacobucci, Bruno Calabretta
Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is currently treated with BCR-ABL1 tyrosine kinase inhibitors (TKI) in combination with chemotherapy. However, most patients develop resistance to TKI through BCR-ABL1-dependent and -independent mechanisms. Newly developed TKI can target Ph+ ALL cells with BCR-ABL1-dependent resistance; however, overcoming BCR-ABL1-independent mechanisms of resistance remains challenging because transcription factors (TF), which are difficult to inhibit, are often involved...
December 12, 2017: Cancer Research
https://www.readbyqxmd.com/read/29232915/histologic-grade-is-predictive-of-incidence-of-epidermal-growth-factor-receptor-mutations-in-metastatic-lung-adenocarcinoma
#20
Michelle Levy, Liisa Lyon, Erika Barbero, John Wong, Marie Suga, Danny Sam, Minggui Pan
Activating epidermal growth factor receptor (EGFR) mutations in metastatic non-small cell lung cancer (NSCLC) are associated with a high response rate to EGFR tyrosine kinase inhibitor (TKI). The current guidelines recommend routine EGFR mutational analysis prior to initiating first line systemic therapy. The clinical characteristics including smoking status, histologic type, sex and ethnicity are known to be associated with the incidence of EGFR mutations. We retrospectively analyzed 277 patients with metastatic NSCLC within Kaiser Permanente Northern California (KPNC); among these patients, 83 were positive for EGFR mutations...
December 11, 2017: Medical Sciences: Open Access Journal
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