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https://www.readbyqxmd.com/read/28259610/vandetanib-plus-gemcitabine-versus-placebo-plus-gemcitabine-in-locally-advanced-or-metastatic-pancreatic-carcinoma-vip-a-prospective-randomised-double-blind-multicentre-phase-2-trial
#1
Gary Middleton, Daniel H Palmer, William Greenhalf, Paula Ghaneh, Richard Jackson, Trevor Cox, Anthony Evans, Victoria E Shaw, Jonathan Wadsley, Juan W Valle, David Propper, Harpreet Wasan, Stephen Falk, David Cunningham, Fareeda Coxon, Paul Ross, Srinivasan Madhusudan, Nick Wadd, Pippa Corrie, Tamas Hickish, Eithne Costello, Fiona Campbell, Charlotte Rawcliffe, John P Neoptolemos
BACKGROUND: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer...
March 1, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28254765/biological-therapies-in-nonsmall-cell-lung-cancer
#2
REVIEW
Jon Zugazagoitia, Sonia Molina-Pinelo, Fernando Lopez-Rios, Luis Paz-Ares
Biological therapies have improved survival outcomes of advanced-stage nonsmall cell lung cancer (NSCLC). Genotype-directed therapies have changed treatment paradigms of patients with EGFR-mutant and ALK/ROS1-rearranged lung adenocarcinomas, and the list of druggable targets with demonstrated clinical actionability (BRAF, MET, RET, NTRK1 and HER2) continues to expand. Furthermore, we have incrementally understood the mechanisms of cancer immune evasion and foresee ways to effectively circumvent them, particularly at the immune checkpoint level...
March 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28242228/protein-s-glutathionylation-alters-superoxide-hydrogen-peroxide-emission-from-pyruvate-dehydrogenase-complex
#3
Marisa O'Brien, Julia Chalker, Liam Slade, Danielle Gardiner, Ryan J Mailloux
Pyruvate dehydrogenase (Pdh) is a vital source of reactive oxygen species (ROS) in several different tissues. Pdh has also been suggested to serve as a mitochondrial redox sensor. Here, we report that O2(•-)/ H2O2 emission from pyruvate dehydrogenase (Pdh) is altered by S-glutathionylation. Glutathione disulfide (GSSG) amplified O2(•-)/ H2O2 production by purified Pdh during reverse electron transfer (RET) from NADH. Thiol oxidoreductase glutaredoxin-2 (Grx2) reversed these effects confirming that Pdh is a target for S-glutathionylation...
February 27, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28236116/clinical-pharmacokinetic-and-pharmacodynamic-profile-of-lenvatinib-an-orally-active-small-molecule-multitargeted-tyrosine-kinase-inhibitor
#4
Ziad Hussein, Hitoshi Mizuo, Seiichi Hayato, Masayuki Namiki, Robert Shumaker
Lenvatinib is a multikinase inhibitor that targets vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor-alpha, and RET and KIT proto-oncogenes. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer in the United States (US), European Union (EU), Canada, Japan, and Switzerland. It is also approved in combination with everolimus for the treatment of advanced renal cell carcinoma following ≥1 VEGF-targeted treatment in the US and EU...
February 24, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28181564/multiplexed-transcriptome-analysis-to-detect-alk-ros1-and-ret-rearrangements-in-lung-cancer
#5
Toni-Maree Rogers, Gisela Mir Arnau, Georgina L Ryland, Stephen Huang, Maruja E Lira, Yvette Emmanuel, Omar D Perez, Darryl Irwin, Andrew P Fellowes, Stephen Q Wong, Stephen B Fox
ALK, ROS1 and RET gene fusions are important predictive biomarkers for tyrosine kinase inhibitors in lung cancer. Currently, the gold standard method for gene fusion detection is Fluorescence In Situ Hybridization (FISH) and while highly sensitive and specific, it is also labour intensive, subjective in analysis, and unable to screen a large numbers of gene fusions. Recent developments in high-throughput transcriptome-based methods may provide a suitable alternative to FISH as they are compatible with multiplexing and diagnostic workflows...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28122586/mir-182-promotes-cancer-invasion-by-linking-ret-oncogene-activated-nf-%C3%AE%C2%BAb-to-loss-of-the-hes1-notch1-regulatory-circuit
#6
Alf Spitschak, Claudia Meier, Bhavani Kowtharapu, David Engelmann, Brigitte M Pützer
BACKGROUND: Dominant-activating mutations in the RET proto-oncogene, a receptor tyrosine kinase, are responsible for the development of medullary thyroid carcinoma (MTC) and causative for multiple endocrine neoplasia (MEN) type 2A and 2B. These tumors are highly aggressive with a high propensity for early metastasis and chemoresistance. This attribute makes this neoplasia an excellent model for probing mechanisms underlying cancer progression. METHODS: The expression level of miR-182 was measured in MTC tumor specimens and in TT cells by real-time RT-PCR...
January 26, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28092668/upregulation-of-ret-induces-perineurial-invasion-of-pancreatic-adenocarcinoma
#7
M Amit, S Na'ara, L Leider-Trejo, Y Binenbaum, N Kulish, E Fridman, A Shabtai-Orbach, R J Wong, Z Gil
Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC). Neural invasion is associated with poor outcome, yet its mechanism remains unclear. Using the transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28073897/identification-of-alk-ros1-and-ret-fusions-by-a-multiplexed-mrna-based-assay-in-formalin-fixed-paraffin-embedded-samples-from-advanced-non-small-cell-lung-cancer-patients
#8
Noemí Reguart, Cristina Teixidó, Ana Giménez-Capitán, Laia Paré, Patricia Galván, Santiago Viteri, Sonia Rodríguez, Vicente Peg, Erika Aldeguer, Nuria Viñolas, Jordi Remon, Niki Karachaliou, Esther Conde, Fernando Lopez-Rios, Ernest Nadal, Sabine Merkelbach-Bruse, Reinhard Büttner, Rafael Rosell, Miguel A Molina-Vila, Aleix Prat
BACKGROUND: Anaplastic lymphoma receptor tyrosine kinase (ALK), ROS protooncogene 1, receptor tyrosine kinase (ROS1), and ret protooncogene (RET) fusions are present in 5%-7% of patients with advanced non-small-cell lung cancer (NSCLC); their accurate identification is critical to guide targeted therapies. FISH and immunohistochemistry (IHC) are considered the gold standards to determine gene fusions, they have limitations. The nCounter platform is a potentially useful genomic tool for multiplexed detection of gene fusions, but has not been validated in the clinical setting...
January 10, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28068878/long-term-control-of-hypercortisolism-by-vandetanib-in-a-case-of-medullary-thyroid-carcinoma-with-a-somatic-ret-mutation
#9
Anne-Cécile Paepegaey, Béatrix Cochand-Priollet, Estelle Louiset, Pierre-Olivier Sarfati, Marco Alifano, Nelly Burnichon, Marie Bienvenu-Perrard, Najiba Lahlou, Léopoldine Bricaire, Lionel Groussin
BACKGROUND: Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies. PATIENT FINDINGS: The case is reported of a 58-year-old man with MTC-related CS resistant to a combination of several anti-cortisolic drugs...
March 13, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28011461/antitumor-activity-of-rxdx-105-in-multiple-cancer-types-with-ret-rearrangements-or-mutations
#10
Gang G Li, Romel Somwar, James Joseph, Roger S Smith, Takuo Hayashi, Leenus Martin, Aleksandra Franovic, Annelie Schairer, Eric S Martin, Gregory J Riely, Jason Harris, Shunqi Yan, Ge Wei, Jennifer Oliver, Rupal Patel, Pratik Multani, Marc Ladanyi, Alexander Drilon
PURPOSE: While multikinase inhibitors with RET activity are active in RET-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by RET alterations...
December 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27994058/signal-transducer-and-activator-of-transcription-1-plays-a-pivotal-role-in-ret-ptc3-oncogene-induced-expression-of-indoleamine-2-3-dioxygenase-1
#11
Sonia Moretti, Elisa Menicali, Nicole Nucci, Pasquale Voce, Renato Colella, Rosa Marina Melillo, Federica Liotti, Silvia Morelli, Francesca Fallarino, Antonio Macchiarulo, Massimo Santoro, Nicola Avenia, Efisio Puxeddu
Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAF(V600E)- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27988109/receptor-tyrosine-kinases-translocation-partners-in-hematopoietic-disorders
#12
REVIEW
Katelyn N Nelson, Malalage N Peiris, April N Meyer, Asma Siari, Daniel J Donoghue
Receptor tyrosine kinases (RTKs) activate various signaling pathways and regulate cellular proliferation, survival, migration, and angiogenesis. Malignant neoplasms often circumvent or subjugate these pathways by promoting RTK overactivation through mutation or chromosomal translocation. RTK translocations create a fusion protein containing a dimerizing partner fused to an RTK kinase domain, resulting in constitutive kinase domain activation, altered RTK cellular localization, upregulation of downstream signaling, and novel pathway activation...
January 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/27935748/atf4-targets-ret-for-degradation-and-is-a-candidate-tumor-suppressor-gene-in-medullary-thyroid-cancer
#13
Rozita Bagheri-Yarmand, Michelle D Williams, Elizabeth G Grubbs, Robert F Gagel
CONTEXT: Medullary thyroid cancer (MTC) is an aggressive tumor that harbors activating mutations of the RET proto-oncogene. We previously reported that RET inhibits transcriptional activity of ATF4, the master regulator of the stress response pathway, to prevent cell death. OBJECTIVE: We hypothesized that loss of function of ATF4 play a role in initiation of MTC. DESIGN: Targeted deletion of ATF4 in mice was used to assess ATF4 function in the thyroid gland...
December 9, 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27922668/dual-inhibition-using-cabozantinib-overcomes-hgf-met-signaling-mediated-resistance-to-pan-vegfr-inhibition-in-orthotopic-and-metastatic-neuroblastoma-tumors
#14
Estelle Daudigeos-Dubus, Ludivine Le Dret, Olivia Bawa, Paule Opolon, Albane Vievard, Irène Villa, Jacques Bosq, Gilles Vassal, Birgit Geoerger
MET is expressed on neuroblastoma cells and may trigger tumor growth, neoangiogenesis and metastasis. MET upregulation further represents an escape mechanism to various anticancer treatments including VEGF signaling inhibitors. We developed in vitro a resistance model to pan-VEGFR inhibition and explored the simultaneous inhibition of VEGFR and MET in neuroblastoma models in vitro and in vivo using cabozantinib, an inhibitor of the tyrosine kinases including VEGFR2, MET, AXL and RET. Resistance in IGR-N91-Luc neuroblastoma cells under continuous in vitro exposure pressure to VEGFR1-3 inhibition using axitinib was associated with HGF and p-ERK overexpression...
January 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/27912827/new-targets-in-non-small-cell-lung-cancer
#15
REVIEW
Soo J Park, Soham More, Ayesha Murtuza, Brian D Woodward, Hatim Husain
With the implementation of genomic technologies into clinical practice, we have examples of the predictive benefit of targeted therapy for oncogene-addicted cancer and identified molecular dependencies in non-small cell lung cancer. The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy. Advances have validated oncogenic driver genes and led to the development of targeted agents...
February 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/27904650/cabozantinib-in-the-treatment-of-advanced-renal-cell-carcinoma-clinical-trial-evidence-and-experience
#16
REVIEW
Jose Manuel Ruiz-Morales, Daniel Y C Heng
The treatment of metastatic renal cell carcinoma (mRCC) is rapidly changing. During first-line treatment with targeted therapy, patients ultimately develop resistance to therapy and the disease progresses. Recently, cabozantinib has demonstrated a better response rate, progression-free survival and overall survival compared with everolimus after failure of prior targeted therapy in patients with advanced or metastatic renal cell carcinoma (RCC). Cabozantinib is a small-molecule tyrosine kinase inhibitor (TKI)...
December 2016: Therapeutic Advances in Urology
https://www.readbyqxmd.com/read/27873490/egf-induced-ret-inhibitor-resistance-in-ccdc6-ret-lung-cancer-cells
#17
Hyun Chang, Ji Hea Sung, Sung Ung Moon, Han Soo Kim, Jin Won Kim, Jong Seok Lee
PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes...
January 2017: Yonsei Medical Journal
https://www.readbyqxmd.com/read/27826534/fusion-gene-and-splice-variant-analyses-in-liquid-biopsies-of-lung-cancer-patients
#18
REVIEW
Cristina Aguado, Ana Giménez-Capitán, Niki Karachaliou, Ana Pérez-Rosado, Santiago Viteri, Daniela Morales-Espinosa, Rafael Rosell
Obtaining a biopsy of solid tumors requires invasive procedures that strongly limit patient compliance. In contrast, a blood extraction is safe, can be performed at many time points during the course disease and encourages appropriate therapy modifications, potentially improving the patient's clinical outcome and quality of life. Fusion of the tyrosine kinase genes anaplastic lymphoma kinase (ALK), C-ROS oncogen 1 (ROS 1), rearranged during transfection (RET) and neurotrophic tyrosine kinase 1 (NTRK1) occur in 1-5% of lung adenocarcinomas and constitute therapeutic targets for tyrosine kinase inhibitors...
October 2016: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/27825638/erlotinib-cabozantinib-or-erlotinib-plus-cabozantinib-as-second-line-or-third-line-treatment-of-patients-with-egfr-wild-type-advanced-non-small-cell-lung-cancer-ecog-acrin-1512-a-randomised-controlled-open-label-multicentre-phase-2-trial
#19
Joel W Neal, Suzanne E Dahlberg, Heather A Wakelee, Seena C Aisner, Michaela Bowden, Ying Huang, David P Carbone, Gregory J Gerstner, Rachel E Lerner, Jerome L Rubin, Taofeek K Owonikoko, Philip J Stella, Preston D Steen, Ahmed Ali Khalid, Suresh S Ramalingam
BACKGROUND: Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC. METHODS: This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA...
December 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27825637/ret-inhibitors-for-patients-with-ret-fusion-positive-and-ret-wild-type-non-small-cell-lung-cancer
#20
Rafael Rosell, Niki Karachaliou
No abstract text is available yet for this article.
December 2016: Lancet Oncology
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