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https://www.readbyqxmd.com/read/28912872/preclinical-trial-of-the-multi-targeted-lenvatinib-in-combination-with-cellular-immunotherapy-for-treatment-of-renal-cell-carcinoma
#1
Chengkuan Cai, Jingyuan Tang, Baixin Shen, Liucheng Ding, Yunpeng Shao, Zhengsen Chen, Yinchao Ma, Haoliang Xue, Zhongqing Wei
Lenvatinib is an oral, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor β, RET and KIT. Cellular immunotherapy has the potential to be a highly targeted treatment, with low toxicity to normal tissues and a high capacity to eradicate tumor tissue. The present study assessed the safety, maximum tolerated dose (MTD) and preliminary antitumor activity of lenvatinib and cellular immunotherapy in a murine model of renal cell carcinoma (RCC)...
October 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28911729/chemotherapy-and-tyrosine-kinase-inhibitors-for-medullary-thyroid-cancer
#2
REVIEW
Julien Hadoux, Martin Schlumberger
Medullary thyroid cancer (MTC) represents 3% of all clinical thyroid cancers and arises from thyroid C cells that produce calcitonin. Locally advanced or metastatic MTC requires a careful work-up including measurement of serum calcitonin and carcinoembryonic antigen, determination of their doubling time and comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for treatment. Cytotoxic chemotherapy can control tumor burden in some patients with response rates of around 20% in old series...
June 2017: Best Practice & Research. Clinical Endocrinology & Metabolism
https://www.readbyqxmd.com/read/28911727/the-molecular-basis-for-ret-tyrosine-kinase-inhibitors-in-thyroid-cancer
#3
REVIEW
Valentina De Falco, Francesca Carlomagno, Hong-Yu Li, Massimo Santoro
RET receptor tyrosine kinase acts as a mutated oncogenic driver in several human malignancies and it is over-expressed in other cancers. Small molecule compounds with RET tyrosine kinase inhibitory activity are being investigated for the targeted treatment of these malignancies. Multi-targeted compounds with RET inhibitory concentration in the nanomolar range have entered clinical practice. This review summarizes mechanisms of RET oncogenic activity and properties of new compounds that, at the preclinical stage, have demonstrated promising anti-RET activity...
June 2017: Best Practice & Research. Clinical Endocrinology & Metabolism
https://www.readbyqxmd.com/read/28881815/clinicopathological-characteristics-of-ros1-and-ret-rearranged-nsclc-in-caucasian-patients-data-from-a-cohort-of-713-non-squamous-nsclc-lacking-kras-egfr-her2-braf-pik3ca-alk-alterations
#4
Frédéric Dugay, Francisco Llamas-Gutierrez, Marjory Gournay, Sarah Medane, François Mazet, Dan Christian Chiforeanu, Emmanuelle Becker, Régine Lamy, Hervé Léna, Nathalie Rioux-Leclercq, Marc-Antoine Belaud-Rotureau, Florian Cabillic
Targeted therapies have substantially changed the management of non-small cell lung cancer (NSCLC) patients with driver oncogenes. Given the high frequency, EGFR and ALK aberrations were the first to be detected and paved the way for tyrosine kinase inhibitor (TKI) treatments. Other kinases such as ROS1 and more recently RET have emerged as promising targets, and ROS1 and RET TKIs are already available for precision medicine. We screened a large cohort of 713 Caucasian non-squamous NSCLC patients lacking EGFR/KRAS/BRAF/HER2/PI3KCA/ALK aberrations for ROS1 and RET rearrangements using fluorescence in situ hybridization to determine the frequency and clinicopathological characteristics of ROS1- and RET-positive patients...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28877471/kif5b-ret-oncoprotein-signals-through-a-multi-kinase-signaling-hub
#5
Tirtha Kamal Das, Ross Leigh Cagan
Gene fusions are increasingly recognized as important cancer drivers. The KIF5B-RET gene has been identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation, including hyperproliferation, epithelial-to-mesenchymal transition, invasion, and extension of striking invadopodia-like processes. The KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation, including invadopodia-like processes...
September 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28857077/fusions-in-solid-tumours-diagnostic-strategies-targeted-therapy-and-acquired-resistance
#6
REVIEW
Alison M Schram, Matthew T Chang, Philip Jonsson, Alexander Drilon
Structural gene rearrangements resulting in gene fusions are frequent events in solid tumours. The identification of certain activating fusions can aid in the diagnosis and effective treatment of patients with tumours harbouring these alterations. Advances in the techniques used to identify fusions have enabled physicians to detect these alterations in the clinic. Targeted therapies directed at constitutively activated oncogenic tyrosine kinases have proven remarkably effective against cancers with fusions involving ALK, ROS1, or PDGFB, and the efficacy of this approach continues to be explored in malignancies with RET, NTRK1/2/3, FGFR1/2/3, and BRAF/CRAF fusions...
August 31, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28840516/deleterious-effects-of-vegfr2-and-ret-inhibition-in-a-preclinical-model-of-parkinson-s-disease
#7
C Requejo, J A Ruiz-Ortega, H Bengoetxea, S Bulnes, L Ugedo, J V Lafuente
Neurotrophic factors (NTFs) are a promising therapeutic option for Parkinson's disease (PD). They exert their function through tyrosine kinase receptors. Our goal was to assess the effects of administering a selective tyrosine kinase inhibitor (vandetanib) that blocks VEGFR2 and RET receptors in a preclinical model of PD. Rats underwent intrastriatal injections of 6-hydroxydopamine (6-OHDA). Two weeks later, the rats received 30 mg/kg vandetanib or saline orally. The effects were assessed using the rotational behavioral test, tyrosine hydroxylase (TH) immunohistochemistry, and western blot...
August 24, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28838400/emergence-of-fgfr3-tacc3-fusions-as-a-potential-by-pass-resistance-mechanism-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutated-nsclc-patients
#8
Sai-Hong Ignatius Ou, Leora Horn, Marcelo Cruz, Davood Vafai, Christine M Lovly, Allison Spradlin, Michael J Williamson, Ibiayi Dagogo-Jack, Adrienne Johnson, Vincent A Miller, Shirish Gadgeel, Siraj M Ali, Alexa B Schrock
Resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) with activating EGFR mutations generally involve development of acquired secondary or tertiary EGFR mutations, such as T790M or C797S. However, case reports have demonstrated that actionable receptor tyrosine kinase fusions such as EML4-ALK, CCDC6-RET, and FGFR3-TACC3 can potentially confer resistance to EGFR TKIs. We seeked to identify the prevalence of FGFR3-TACC3 fusion transcripts as resistance mechanism to EGFR TKIs...
September 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28802831/validation-of-a-targeted-rna-sequencing-assay-for-kinase-fusion-detection-in-solid-tumors
#9
Julie W Reeser, Dorrelyn Martin, Jharna Miya, Esko A Kautto, Ezra Lyon, Eliot Zhu, Michele R Wing, Amy Smith, Matthew Reeder, Eric Samorodnitsky, Hannah Parks, Karan R Naik, Joseph Gozgit, Nicholas Nowacki, Kurtis D Davies, Marileila Varella-Garcia, Lianbo Yu, Aharon G Freud, Joshua Coleman, Dara L Aisner, Sameek Roychowdhury
Kinase gene fusions are important drivers of oncogenic transformation and can be inhibited with targeted therapies. Clinical grade diagnostics using RNA sequencing to detect gene rearrangements in solid tumors are limited, and the few that are available require prior knowledge of fusion break points. To address this, we have analytically validated a targeted RNA sequencing assay (OSU-SpARKFuse) for fusion detection that interrogates complete transcripts from 93 kinase and transcription factor genes. From a total of 74 positive and 36 negative control samples, OSU-SpARKFuse had 93...
August 8, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28796396/development-of-ret-mutant-cutaneous-angiosarcoma-during-braf-inhibitor-therapy
#10
Julia Dai, Christian A Kunder, Emily Y Chu, Edward Chan, Christine L Egan, Roberto A Novoa
Treatment with BRAF inhibitors may lead to paradoxical mitogen-activated protein kinase (MAPK) pathway activation and accelerated tumorigenesis in cells with preexisting oncogenic hits. This phenomenon manifests clinically in the development of squamous cell carcinomas (SCCs) and keratoacanthomas (KAs) in patients treated with BRAF inhibitors. Cases of extracutaneous malignancies associated with BRAF inhibitors have also been reported. We present a case of a patient who developed a cutaneous angiosarcoma six months after initiation of vemurafenib therapy...
August 10, 2017: Journal of Cutaneous Pathology
https://www.readbyqxmd.com/read/28795691/evaluation-of-in-vitro-and-in-vivo-activity-of-a-multityrosine-kinase-inhibitor-al3810-against-human-thyroid-cancer
#11
Qin Xie, Hui Chen, Jing Ai, Ying-Lei Gao, Mei-Yu Geng, Jian Ding, Yi Chen
Thyroid cancer is the most common type of endocrine neoplasia. Despite recent breakthroughs in treatment of the disease, the treatment of advanced, progressive thyroid cancers remains challenging with limited therapeutic options available. In this study, we evaluated a novel and orally bioavailable small-molecule multiple tyrosine kinases inhibitor, AL3810, in preclinical models of thyroid cancer in vitro and in vivo. AL3810 (2-5 μmol/L) dose-dependently inhibited the proliferation of human thyroid cancer cell lines TT, SW579 and TPC-1 in vitro with IC50 values ranging from 0...
August 10, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28751462/selective-met-kinase-inhibition-in-met-dependent-glioma-models-alters-gene-expression-and-induces-tumor-plasticity
#12
Corina N A M van den Heuvel, Anna C Navis, Tessa de Bitter, Houshang Amiri, Kiek Verrijp, Arend Heerschap, Karen Rex, Isabelle Dussault, Sean Caenepeel, Angela Coxon, Paul N Span, Pieter Wesseling, Wiljan Hendriks, William P J Leenders
The receptor tyrosine kinase (RTK) MET represents a promising tumor target in a subset of glioblastomas. Most RTK inhibitors available in the clinic today, including those inhibiting MET, affect multiple targets simultaneously. Previously, it was demonstrated that treatment with cabozantinib (MET/VEGFR2/RET inhibitor) prolonged survival of mice carrying orthotopic patient-derived xenografts (PDX) of the MET-addicted glioblastoma model E98, yet did not prevent development of recurrent and cabozantinib-resistant tumors...
July 27, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28714692/design-synthesis-and-pharmacological-evaluation-of-novel-multisubstituted-pyridin-3-amine-derivatives-as-multitargeted-protein-kinase-inhibitors-for-the-treatment-of-non-small-cell-lung-cancer
#13
Wei Zhu, Hui Chen, Yulan Wang, Jiang Wang, Xia Peng, Xianjie Chen, Yinglei Gao, Chunpu Li, Yulong He, Jing Ai, Meiyu Geng, Mingyue Zheng, Hong Liu
A novel series of pyridin-3-amine derivatives were designed, synthesized, and evaluated as multitargeted protein kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC). Hit 1 was first disclosed by in silico screening against fibroblast growth factor receptors (FGFR), which was subsequently validated by in vitro experiments. The structure-activity relationship (SAR) of its analogues was then explored to afford novel FGFR inhibitors 2a-2p and 3a-3q. Among them, 3m showed potent inhibition against FGFR1, 2, and 3...
July 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28676214/dna-mismatch-repair-deficiency-in-surgically-resected-lung-adenocarcinoma-microsatellite-instability-analysis-using-the-promega-panel
#14
Kazuya Takamochi, Fumiyuki Takahashi, Yoshiyuki Suehara, Eiichi Sato, Shinji Kohsaka, Takuo Hayashi, Shigehisa Kitano, Toshihide Uneno, Shinya Kojima, Kengo Takeuchi, Hiroyuki Mano, Kenji Suzuki
OBJECTIVES: DNA mismatch repair (MMR) deficiency has recently received increasing attention as a significant biomarker to predict the treatment effect of immune checkpoint inhibitors for various malignant neoplasms. To evaluate MMR status, we analyzed the microsatellite instability (MSI) of lung adenocarcinomas. MATERIALS AND METHODS: Frozen tissues of lung adenocarcinoma and corresponding normal lung were obtained from 341 patients, including 141 with tumors harboring driver gene alterations (50 EGFR gene mutations, 50 KRAS gene mutations, 21 ALK fusions, 10 ROS1 fusions, and 10 RET fusions) and 200 with pan-negative tumors (100 never- or light-smokers and 100 heavy-smokers), who were surgically treated between 2007 and 2015...
August 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28658345/medullary-thyroid-carcinoma-adverse-events-during-systemic-treatment-risk-benefit-ratio
#15
Léa Maria Zanini Maciel, Patrícia Künzle Ribeiro Magalhães
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells of the thyroid and associated with mutations in the proto-oncogene REarranged during Transfection (RET). The prognosis of MTC depends on clinical stage, with a 95.6% 10-year survival rate among patients with localized disease and 40% among patients with advanced disease. Standard chemotherapy and radiotherapy have no significant impact on the overall survival of these patients and two tyrosine kinase receptor inhibitors (TKIs), vandetanib and cabozantinib, have been recently approved for the systemic treatment of locally advanced or metastatic MTC...
June 26, 2017: Archives of Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28650002/cabozantinib-use-in-renal-cell-carcinoma
#16
REVIEW
A J Neuwelt, S Mathur, A T Johnson, E R Kessler, D W Bowles
In the last several years, many new drugs have been approved to treat metastatic renal cell carcinoma (RCC). Cabozantinib is a novel multikinase inhibitor with activity against vascular endothelial growth factor receptor (VEGFR), proto-oncogene tyrosine-protein kinase receptor Ret and other kinases that recently joined this impressive list of approved agents. Cabozantinib is an active agent in the preclinical and clinical setting, having recently demonstrated superiority over everolimus in a blinded, randomized phase III study of patients with progressive RCC after at least one prior line of antiangiogenic therapy...
May 2017: Drugs of Today
https://www.readbyqxmd.com/read/28639308/discovery-of-wt-ret-and-v804m-ret-inhibitors-from-hit-to-lead
#17
Luca Mologni, Martina Dalla Via, Adriana Chilin, Manlio Palumbo, Giovanni Marzaro
Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET ((wt) RET) and its mutants (e.g., (V804M) RET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar (wt) RET/(V804M) RET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2''-benzamido)pyridin-4''-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound...
June 22, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28637019/clinicopathological-characteristics-of-ros1-and-ret-rearranged-nsclc-in-caucasian-patients-data-from-a-cohort-of-713-non-squamous-nsclc-lacking-kras-egfr-her2-braf-pik3ca-alk-alterations
#18
Frédéric Dugay, Francisco Llamas-Gutierrez, Marjory Gournay, Sarah Medane, François Mazet, Dan Christian Chiforeanu, Emmanuelle Becker, Régine Lamy, Hervé Léna, Nathalie Rioux-Leclercq, Marc-Antoine Belaud-Rotureau, Florian Cabillic
Targeted therapies have substantially changed the management of non-small cell lung cancer (NSCLC) patients with driver oncogenes. Given the high frequency, EGFR and ALK aberrations were the first to be detected and paved the way for tyrosine kinase inhibitor (TKI) treatments. Other kinases such as ROS1 and more recently RET have emerged as promising targets, and ROS1 and RET TKIs are already available for precision medicine.We screened a large cohort of 713 Caucasian non-squamous NSCLC patients lacking EGFR/KRAS/BRAF/HER2/PI3KCA/ALK aberrations for ROS1 and RET rearrangements using fluorescence in situ hybridization to determine the frequency and clinicopathological characteristics of ROS1- and RET-positive patients...
June 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28615362/drugging-the-catalytically-inactive-state-of-ret-kinase-in-ret-rearranged-tumors
#19
Dennis Plenker, Maximilian Riedel, Johannes Brägelmann, Marcel A Dammert, Rakhee Chauhan, Phillip P Knowles, Carina Lorenz, Marina Keul, Mike Bührmann, Oliver Pagel, Verena Tischler, Andreas H Scheel, Daniel Schütte, Yanrui Song, Justina Stark, Florian Mrugalla, Yannic Alber, André Richters, Julian Engel, Frauke Leenders, Johannes M Heuckmann, Jürgen Wolf, Joachim Diebold, Georg Pall, Martin Peifer, Maarten Aerts, Kris Gevaert, René P Zahedi, Reinhard Buettner, Kevan M Shokat, Neil Q McDonald, Stefan M Kast, Oliver Gautschi, Roman K Thomas, Martin L Sos
Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors...
June 14, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28585189/modulatory-role-of-nurr1-activation-and-thrombin-inhibition-in-the-neuroprotective-effects-of-dabigatran-etexilate-in-rotenone-induced-parkinson-s-disease-in-rats
#20
Esraa A Kandil, Rabab H Sayed, Lamiaa A Ahmed, Mai A Abd El Fattah, Bahia M El-Sayeh
Recently, it has been shown that both decreased nuclear receptor-related 1 (Nurr1) expression and thrombin accumulation are involved in the degeneration of dopaminergic neurons in Parkinson's disease (PD). The new anticoagulant dabigatran etexilate (DE) is a direct thrombin inhibitor that owns benzimidazole group, which has been proposed to activate Nurr1. In the present study, we examined the neuroprotective effects of DE in rotenone model of PD. Rotenone was injected subcutaneously at a dose of 1.5 mg/kg every other day for 21 days...
June 5, 2017: Molecular Neurobiology
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