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https://www.readbyqxmd.com/read/29136674/familial-hyperparathyroidism-disorders-of-growth-and-secretion-in-hormone-secretory-tissue
#1
Stephen J Marx, Delmar Muniz Lourenco
Six syndromes of familial hyperparathyroidism are compared: 1) Familial hypocalciuric hypercalcemia (FHH) expresses primary hyperparathyroidism (PHPT) beginning at birth with lifelong hypercalcemia. There is nonsuppressed PTH secretion from outwardly normal parathyroid glands. It reflects germline heterozygous mutation in CASR, GNA11, or AP2S1. 2) Neonatal severe primary hyperparathyroidism is severest of the six syndromes. It requires urgent total parathyroidectomy in infancy. It usually reflects biallelic inactivation of the CASR...
November 2017: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/29134959/targeting-ret-driven-cancers-lessons-from-evolving-preclinical-and-clinical-landscapes
#2
REVIEW
Alexander Drilon, Zishuo I Hu, Gillianne G Y Lai, Daniel S W Tan
The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers or RET-mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAF(V600E) mutations, or ALK or ROS1 rearrangements...
November 14, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29133048/structural-optimization-and-structure-activity-relationship-studies-of-n-phenyl-7-8-dihydro-6h-pyrimido-5-4-b-1-4-oxazin-4-amine-derivatives-as-a-new-class-of-inhibitors-of-ret-and-its-drug-resistance-mutants
#3
Jiao Yang, Kai Chen, Guo Zhang, Qiu-Yuan Yang, Yue-Shan Li, Shen-Zhen Huang, Yan-Lin Wang, Wei Yang, Xiao-Juan Jiang, Heng-Xiu Yan, Jing-Qiang Zhu, Rong Xiang, You-Fu Luo, Wei-Min Li, Yu-Quan Wei, Lin-Li Li, Sheng-Yong Yang
The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants...
September 15, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29128428/clinical-and-translational-implications-of-ret-rearrangements-in-non-small-cell-lung-cancer
#4
REVIEW
Roberto Ferrara, Nathalie Auger, Edouard Auclin, Benjamin Besse
Since the discovery in 2012 of RET rearrangements in non-small cell lung cancer (NSCLC), at least 12 different fusion variants have been identified, with KIF5B-RET being the most frequent and the best characterized. Unlike ALK and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry, although fluorescence in situ hybridization and reverse transcriptase PCR are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histology, never-smoking status, younger age, more advanced stage disease, potentially higher chemo-sensitivity (in particular to pemetrexed-based regimens), and coexistence of other genomic alterations...
November 8, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29125548/liquid-biopsy-and-therapeutic-targets-present-and-future-issues-in-thoracic-oncology
#5
REVIEW
Paul Hofman
The practice of liquid biopsy (LB) has revolutionized the care of patients with metastatic lung cancer. Many oncologists now use this approach in daily practice, applying precise procedures for the detection of activating or resistance mutations in EGFR. These tests are performed with plasma DNA and have been approved as companion diagnostic test for patients treated with tyrosine kinase inhibitors. ALK is another important target in lung cancer since it leads to treatment of patients who are positive for a rearrangement in ALK identified with tumor tissue...
November 10, 2017: Cancers
https://www.readbyqxmd.com/read/29114472/molecular-diagnostics-of-lung-cancer-in-the-clinic
#6
REVIEW
Lynette Sholl
According to current practice guidelines, all patients with advanced non-small cell lung cancer (NSCLC) should undergo predictive biomarker testing. For squamous cell carcinoma patients, PD-L1 immunohistochemistry is indicated to select patients for immunotherapy in the first line. For lung adenocarcinoma, all patients with advanced disease should undergo testing for epidermal growth factor receptor (EGFR) mutations, ALK and ROS1 rearrangements, and PD-L1 expression to predict response to EGFR, ALK, or ROS1 targeted inhibitors or immunotherapy, respectively...
October 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/29106982/distinct-trka-and-ret-modulated-negative-and-positive-neuropathic-behaviors-in-a-mouse-model-of-resiniferatoxin-induced-small-fiber-neuropathy
#7
Yu-Lin Hsieh, Hung-Wei Kan, Hao Chiang, Yi-Chen Lee, Sung-Tsang Hsieh
Neurotrophic factors and their corresponding receptors play key roles in the maintenance of different phenotypic dorsal root ganglion (DRG) neurons, the axons of which degenerate in small fiber neuropathy, leading to various neuropathic manifestations. Mechanisms underlying positive and negative symptoms of small fiber neuropathy have not been systematically explored. This study investigated the molecular basis of these seemingly paradoxical neuropathic behaviors according to the profiles of TrkA and Ret with immunohistochemical and pharmacological interventions in a mouse model of resiniferatoxin (RTX)-induced small fiber neuropathy...
October 26, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/29097733/discovery-of-targetable-genetic-alterations-in-advanced-non-small-cell-lung-cancer-using-a-next-generation-sequencing-based-circulating-tumor-dna-assay
#8
Helei Hou, Xiaonan Yang, Jinping Zhang, Zhe Zhang, Xiaomei Xu, Xiaoping Zhang, Chuantao Zhang, Dong Liu, Weihua Yan, Na Zhou, Hongmei Zhu, Zhaoyang Qian, Zhuokun Li, Xiaochun Zhang
Next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) assays have provided a new method of identifying tumor-driving genes in patients with advanced non-small cell lung carcinoma (NSCLC), especially in those whose cancer tissues are unavailable or in those that have acquired treatment resistance. Here, we describe a total of 119 patients with advanced EGFR-TKI-naive NSCLC and 15 EGFR-TKI-resistant patients to identify somatic SNVs, small indels, CNVs and gene fusions in 508 tumor-related genes...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29066909/case-report-of-a-kit-mutated-melanoma-patient-with-an-excellent-response-to-apatinib-and-temozolomide-combination-therapy
#9
Cong Luo, Jiayu Shen, Jieer Ying, Xianhua Fang, Xiaohong Wang, Zhixuan Fu, Peng Liu
Malignant melanoma is one kind of malignant disease which has high rates of mortality, metastasis, and poor prognosis. The therapeutic landscape is rapidly changing with the development of novel agents in recent decades, such as anti-PD-1 agents, anti-CTLA-4 agents, and BRAF inhibitors. However, since most of these novel agents are very expensive, not all patients can afford them. Apatinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2) and may also be effective on Ret, c-KIT, and c-src...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29059635/phase-ii-randomised-discontinuation-trial-of-cabozantinib-in-patients-with-advanced-solid-tumours
#10
Patrick Schöffski, Michael Gordon, David C Smith, Razelle Kurzrock, Adil Daud, Nicholas J Vogelzang, Yihua Lee, Christian Scheffold, Geoffrey I Shapiro
BACKGROUND: Cabozantinib is an inhibitor of tyrosine kinases, including MET, vascular endothelial growth factor receptor, AXL and RET. This multi-cohort phase II randomised discontinuation trial explored anticancer activity of cabozantinib in nine tumour types. PATIENTS AND METHODS: Cabozantinib was administered (100 mg, once daily) to patients with advanced, recurrent or metastatic cancers. Those with stable disease at week 12 were randomised 1:1 to cabozantinib or placebo...
October 20, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#11
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
September 19, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29044514/ccdc6-the-identity-of-a-protein-known-to-be-partner-in-fusion
#12
REVIEW
Aniello Cerrato, Francesco Merolla, Francesco Morra, Angela Celetti
Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types...
October 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29039585/identification-of-genome-variations-in-patients-with-lung-adenocarcinoma-using-whole-genome-re%C3%A2-sequencing
#13
Guiyuan Li, Yunqing Mei, Fan Yang, Shengming Yi, Lemin Wang
Lung adenocarcinoma is one of the types of non‑small cell lung carcinoma, which tends to be treated with surgical therapy rather than radiation therapy. It occurs in smokers and non‑smokers, and is the most common form of lung cancer among non‑smokers and women. Gene rearrangements, including ALK, ROS1 and RET, and gene mutations, including epidermal growth factor receptor (EGFR), HER2, Kristen rat sarcoma viral oncogene homolog, BRAF, phosphoinositide‑3‑kinase, catalytic, α polypeptide and MET, have been identified in lung adenocarcinoma, which enable targeted therapy in lung adenocarcinoma, for example erlotinib, gefitinib and afatinib, which are EGFR inhibitors...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29025983/predictive-value-of-fdg-pet-in-patients-with-advanced-medullary-thyroid-carcinoma-treated-with-vandetanib
#14
Rudolf A Werner, Jan Stefan Schmid, Takahiro Higuchi, Mehrbod Som Javadi, Steven P Rowe, Bruno Märkl, Christoph Aulmann, Martin Fassnacht, Matthias Kroiss, Christoph Reiners, Andreas K Buck, Michael Kreissl, Constantin Lapa
Introduction: Therapeutic options in advanced medullary thyroid carcinoma (MTC) have markedly improved since the introduction of tyrosine kinase inhibitors (TKI). We aimed to assess the role of metabolic imaging using 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) shortly before and 3 months after initiation of TKI treatment. Methods: Eighteen patients with advanced and progressive MTC scheduled for vandetanib treatment underwent baseline (18)F-FDG PET/CT prior to and 3 months after TKI treatment initiation...
October 12, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28990511/sunitinib-in-the-treatment-of-thyroid-cancer
#15
Ferrari Silvia Martinaa, Centanni Marco, Virili Camilla, Miccoli Mario, Ferrari Paola, Ruffilli Ilaria, Ragusa Francesca, Antonelli Alessandro, Fallahi Poupak
BACKGROUND: Sunitinib (SU11248) is an oral, small-molecule, multi-targeted tyrosine kinase inhibitor (TKI), that inhibits receptors for platelet-derived growth factor (PDGF-Rs) and vascular endothelial growth factor receptors (VEGFRs), c-KIT, fms-related tyrosine kinase 3 (FLT3) and RET. The concurrent inhibition of these pathways reduces tumor vascularization and causes cancer cell apoptosis, inducing a tumor shrinkage. Sunitinib is approved for the treatment of imatinib-resistant gastrointestinal stromal tumor (GIST), renal carcinoma, and pancreatic neuroendocrine tumors...
October 6, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28979811/a-novel-multi-target-inhibitor-harboring-selectivity-of-inhibiting-egfr-t790m-sparing-wild-type-egfr
#16
Xiaoping Song, Xin Qi, Qiang Wang, Weiming Zhu, Jing Li
Non-Small Cell Lung Cancer (NSCLC) is driven by a variety of deregulated kinases and the development of multi-target inhibitor for multiple signaling pathways or multiple steps is required. Here, we reported that ZWM026, an indolocarbazoles analogue, derived from mangrove in coastal marine wetland, exhibited selectivity and reversibility against T790M mutant over wild-type EGFR in naturally occurring NSCLC cells and constructed NIH-3T3 cells. It simultaneously inhibited activities of HER2, HER3, HER4 and RET but was different from current multi-target kinase inhibitors...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28979142/the-non-small-cell-lung-cancer-egfr-extracellular-domain-mutation-m277e-is-oncogenic-and-drug-sensitive
#17
Su Yu, Yang Zhang, Yunjian Pan, Chao Cheng, Yihua Sun, Haiquan Chen
PURPOSE: To identify novel oncogenic mutations in non-small cell lung cancer patient specimens that lack mutations in known targetable genes ("pan-negative" patients). METHODS: Comprehensive mutational analyses were performed on 1,356 lung adenocarcinoma specimens. In this cohort of patients, common lung cancer oncogenic driver mutations were detected in the epidermal growth factor receptor (EGFR) kinase domain, the human epidermal growth factor receptor 2 kinase domain, as well as the KRAS, BRAF, ALK, ROS1 and RET genes...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28955006/phase-i-ii-study-of-alectinib-in-lung-cancer-with-ret-fusion-gene-study-protocol
#18
Shinji Takeuchi, Toshinori Murayama, Kenichi Yoshimura, Takahiro Kawakami, Shizuko Takahara, Yasuhito Imai, Yoshikazu Kuribayashi, Katsuhiko Nagase, Koichi Goto, Makoto Nishio, Yoshinori Hasegawa, Miyako Satouchi, Katsuyuki Kiura, Takashi Seto, Seiji Yano
BACKGROUND: The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. METHODS/DESIGN: RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design...
2017: Journal of Medical Investigation: JMI
https://www.readbyqxmd.com/read/28912872/preclinical-trial-of-the-multi-targeted-lenvatinib-in-combination-with-cellular-immunotherapy-for-treatment-of-renal-cell-carcinoma
#19
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
#20
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
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