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https://www.readbyqxmd.com/read/29245078/analysis-of-nras-gain-in-657-patients-with-melanoma-and-evaluation-of-its-sensitivity-to-a-mek-inhibitor
#1
Junya Yan, Xiaowen Wu, Jiayi Yu, Huan Yu, Tianxiao Xu, Kevin M Brown, Xue Bai, Jie Dai, Meng Ma, Huan Tang, Lu Si, Zhihong Chi, Xinan Sheng, Chuanliang Cui, Yan Kong, Jun Guo
BACKGROUND: Neuroblastoma rat-sarcoma (NRAS) mutations have been described in Chinese patients with melanoma. However, the status and the clinical significance of NRAS gain have not been investigated on a large scale. METHODS: A total of 657 melanoma samples were included in the study. NRAS copy number was examined using the QuantiGene Plex DNA assay. The sensitivities of cell lines and patient-derived xenograft (PDX) models containing NRAS gain to a MAP/ERK kinase (MEK) inhibitor (binimetinib) were also evaluated...
December 11, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29245013/combination-cancer-therapy-can-confer-benefit-via-patient-to-patient-variability-without-drug-additivity-or-synergy
#2
Adam C Palmer, Peter K Sorger
Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts...
December 14, 2017: Cell
https://www.readbyqxmd.com/read/29242606/murine-stroma-adopts-a-human-like-metabolic-phenotype-in-the-pdx-model-of-colorectal-cancer-and-liver-metastases
#3
Arnaud Blomme, Gaetan Van Simaeys, Gilles Doumont, Brunella Costanza, Justine Bellier, Yukihiro Otaka, Félicie Sherer, Pierre Lovinfosse, Sébastien Boutry, Ana Perez Palacios, Edwin De Pauw, Touko Hirano, Takehiko Yokobori, Roland Hustinx, Akeila Bellahcène, Philippe Delvenne, Olivier Detry, Serge Goldman, Masahiko Nishiyama, Vincent Castronovo, Andrei Turtoi
Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine counterpart. In the present work we aimed at clarifying the significance of the human-to-murine stromal replacement for the fidelity of colorectal cancer (CRC) and liver metastasis (CRC-LM) PDX model. We have conducted a comparative metabolic analysis between 6 patient tumors and corresponding PDX across 4 generations...
December 15, 2017: Oncogene
https://www.readbyqxmd.com/read/29242316/colorectal-cancer-consensus-molecular-subtypes-translated-to-preclinical-models-uncover-potentially-targetable-cancer-cell-dependencies
#4
Anita Sveen, Jarle Bruun, Peter W Eide, Ina A Eilertsen, Lorena Ramirez, Astrid Murumägi, Mariliina A Arjama, Stine A Danielsen, Kushtrim Kryeziu, Elena Elez, Josep Tabernero, Justin Guinney, Hector G Palmer, Arild Nesbakken, Olli Kallioniemi, Rodrigo Dienstmann, Ragnhild A Lothe
PURPOSE: Response to standard oncological treatment is limited in colorectal cancer (CRC). The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing, however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. EXPERIMENTAL DESIGN: We analyzed CMS in primary CRCs, cell lines and patient-derived xenografts (PDXs). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n=459 drugs) to analyze subtype-specific drug sensitivities...
December 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29239690/antibody-drug-conjugates-design-and-development-for-therapy-and-imaging-in-and-beyond-cancer-labex-mabimprove-industrial-workshop-july-27-28-2017-tours-france
#5
Camille Martin, Claire Kizlik-Masson, André Pèlegrin, Hervé Watier, Marie-Claude Viaud-Massuard, Nicolas Joubert
The annual "Antibody Industrial Symposium", co organized by LabEx MAbImprove, MabDesign and Polepharma, was held in Tours, France on June 27-28, 2017. The focus was on antibody-drug-conjugates (ADCs), new entities which realize the hope of Paul Ehrlich's magic bullet. ADCs result from the bioconjugation of a highly cytotoxic drug to a selective monoclonal antibody, which acts as a vector. Building on knowledge gained during the development of three approved ADCs, brentuximab vedotin (Adcetris®), ado trastuzumab emtansine (Kadcyla®) and inotuzumab ozogamicin (Besponsa®), and the many ADCs in development, this meeting addressed strategies and the latest innovations in the field from fundamental research to manufacturing...
December 14, 2017: MAbs
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
#6
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/29237470/gimatecan-exerts-potent-antitumor-activity-against-gastric-cancer-in-vitro-and-in-vivo-via-akt-and-mapk-signaling-pathways
#7
Zuhua Chen, Zhentao Liu, Wenwen Huang, Zhongwu Li, Jianling Zou, Jingyuan Wang, Xiaoting Lin, Beifang Li, Dongshao Chen, Yanting Hu, Jiafu Ji, Jing Gao, Lin Shen
BACKGROUND: We investigated antitumor activity and underlying mechanisms of DNA topoisomerase I (TopI) inhibitor gimatecan and irinotecan in gastric cancer (GC) in vitro cell lines and in vivo patient-derived xenograft (PDX) models. METHODS: GC cell lines SNU-1, HGC27, MGC803 and NCI-N87 were used to evaluate cell viability and apoptosis after gimatecan or irinotecan treatment, using a cell proliferation assay and flow cytometry, respectively. DNA TopI expression and critical molecules of PI3K/AKT, MAPK and apoptosis signaling pathways were analyzed with western blot...
December 13, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29233821/activity-of-the-pi3k-%C3%AE-%C3%AE-inhibitor-duvelisib-in-a-phase-i-trial-and-preclinical-models-of-t-cell-lymphoma
#8
Steven M Horwitz, Raphael Koch, Pierluigi Porcu, Yasuhiro Oki, Alison Moskowitz, Megan Perez, Patricia Myskowski, Adam Officer, Jacob D Jaffe, Sara N Morrow, Kerstin Allen, Mark Douglas, Howard Stern, Jennifer Sweeney, Patrick Kelly, Virginia Kelly, Jon C Aster, David Weaver, Francine M Foss, David M Weinstock
Duvelisib (IPI-145) is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making Duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a Phase 1, open-label study of Duvelisib in patients with relapsed or refractory PTCL [n=16] and CTCL [n=19], along with in vitro and in vivo models of TCL...
December 12, 2017: Blood
https://www.readbyqxmd.com/read/29230817/ebv-encoded-mirnas-target-atm-mediated-response-in-nasopharyngeal-carcinoma
#9
Raymond W-M Lung, Pok-Man Hau, Ken H-O Yu, Kevin Y Yip, Joanna H-M Tong, W-P Chak, Anthony W-H Chan, Ka-Hei Lam, Angela K-F Lo, Edith K-Y Tin, Shuk-Ling Chau, Jesse C-S Pang, Johnny S-H Kwan, Pierre Busson, Lawrence S Young, Lee-Fah Yap, Sai-Wah Tsao, Ka-Fai To, Kwok-Wai Lo
Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing...
December 12, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/29230350/spatially-graded-hydrogels-for-preclinical-testing-of-glioblastoma-anticancer-therapeutics
#10
S Pedron, H Polishetty, A M Pritchard, B P Mahadik, J N Sarkaria, B A C Harley
While preclinical models such as orthotopic tumors generated in mice from patient-derived specimens are widely used to predict sensitivity or therapeutic interventions for cancer, such xenografts can be slow, require extensive infrastructure, and can make in situ assessment difficult. Such concerns are heightened in highly aggressive cancers, such as glioblastoma (GBM), that display genetic diversity and short mean survival. Biomimetic biomaterial technologies offer an approach to create ex vivo models that reflect biophysical features of the tumor microenvironment (TME)...
September 2017: MRS Communications
https://www.readbyqxmd.com/read/29230043/nanoparticle-orientation-to-control-rna%C3%A2-loading-and-ligand-display-on-extracellular-vesicles-for-cancer-regression
#11
Fengmei Pi, Daniel W Binzel, Tae Jin Lee, Zhefeng Li, Meiyan Sun, Piotr Rychahou, Hui Li, Farzin Haque, Shaoying Wang, Carlo M Croce, Bin Guo, B Mark Evers, Peixuan Guo
Nanotechnology offers many benefits, and here we report an advantage of applying RNA nanotechnology for directional control. The orientation of arrow-shaped RNA was altered to control ligand display on extracellular vesicle membranes for specific cell targeting, or to regulate intracellular trafficking of small interfering RNA (siRNA) or microRNA (miRNA). Placing membrane-anchoring cholesterol at the tail of the arrow results in display of RNA aptamer or folate on the outer surface of the extracellular vesicle...
December 11, 2017: Nature Nanotechnology
https://www.readbyqxmd.com/read/29228696/mp0250-a-vegf-and-hgf-neutralizing-darpin%C3%A2-molecule-shows-high-anti-tumor-efficacy-in-mouse-xenograft-and-patient-derived-tumor-models
#12
Ulrike Fiedler, Savira Ekawardhani, Andreas Cornelius, Pat Gilboy, Talitha R Bakker, Ignacio Dolado, Michael T Stumpp, Keith M Dawson
Background: The VEGF/VEGFR and the HGF/cMET pathways are key mediators of the interplay of tumor cells and their microenvironment. However, inhibition of VEGF has been shown to produce only limited clinical benefit and inhibition of the activation of cMET by HGF has not translated into clinical benefit in pivotal trials. MP0250, a DARPin® molecule that specifically inhibits both VEGF and HGF has been developed to explore the clinical potential of dual inhibition of these pathways. Results: MP0250 binding to VEGF and HGF inhibited downstream signalling through VEGFR2 and cMET resulting in inhibition of proliferation of VEGF- and HGF-dependent cells...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228593/proteasome-inhibitor-bortezomib-enhances-the-effect-of-standard-chemotherapy-in-small-cell-lung-cancer
#13
Sanaz Taromi, Florentine Lewens, Ruza Arsenic, Dagmar Sedding, Jörg Sänger, Almut Kunze, Markus Möbs, Joana Benecke, Helma Freitag, Friederike Christen, Daniel Kaemmerer, Amelie Lupp, Mareike Heilmann, Hedwig Lammert, Claus-Peter Schneider, Karen Richter, Michael Hummel, Britta Siegmund, Meike Burger, Franziska Briest, Patricia Grabowski
Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29221181/analysis-of-ctcl-cell-lines-reveals-important-differences-between-mycosis-fungoides-s%C3%A3-zary-syndrome-vs-htlv-1-leukemic-cell-lines
#14
Elena Netchiporouk, Jennifer Gantchev, Matthew Tsang, Philippe Thibault, Andrew K Watters, John-Douglas Matthew Hughes, Feras M Ghazawi, Anders Woetmann, Niels Ødum, Denis Sasseville, Ivan V Litvinov
HTLV-1 is estimated to affect ~20 million people worldwide and in ~5% of carriers it produces Adult T-Cell Leukemia/Lymphoma (ATLL), which can often masquerade and present with classic erythematous pruritic patches and plaques that are typically seen in Mycosis Fungoides (MF) and Sézary Syndrome (SS), the most recognized variants of Cutaneous T-Cell Lymphomas (CTCL). For many years the role of HTLV-1 in the pathogenesis of MF/SS has been hotly debated. In this study we analyzed CTCL vs. HTLV-1+ leukemic cells...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29212525/establishing-and-characterizing-patient-derived-xenografts-using-pre-chemotherapy-percutaneous-biopsy-and-post-chemotherapy-surgical-samples-from-a-prospective-neoadjuvant-breast-cancer-study
#15
Jia Yu, Bo Qin, Ann M Moyer, Jason P Sinnwell, Kevin J Thompson, John A Copland, Laura A Marlow, James L Miller, Ping Yin, Bowen Gao, Katherine Minter-Dykhouse, Xiaojia Tang, Sarah A McLaughlin, Alvaro Moreno-Aspitia, Anthony Schweitzer, Yan Lu, Jason Hubbard, Donald W Northfelt, Richard J Gray, Katie Hunt, Amy L Conners, Vera J Suman, Krishna R Kalari, James N Ingle, Zhenkun Lou, Daniel W Visscher, Richard Weinshilboum, Judy C Boughey, Matthew P Goetz, Liewei Wang
BACKGROUND: Patient-derived xenografts (PDXs) are increasingly used in cancer research as a tool to inform cancer biology and drug response. Most available breast cancer PDXs have been generated in the metastatic setting. However, in the setting of operable breast cancer, PDX models both sensitive and resistant to chemotherapy are needed for drug development and prospective data are lacking regarding the clinical and molecular characteristics associated with PDX take rate in this setting...
December 6, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29209570/car-t-cell-immunotherapy-of-met-expressing-malignant-mesothelioma
#16
Thivyan Thayaparan, Roseanna M Petrovic, Daniela Y Achkova, Tomasz Zabinski, David M Davies, Astero Klampatsa, Ana C Parente-Pereira, Lynsey M Whilding, Sjoukje Jc van der Stegen, Natalie Woodman, Michael Sheaff, Jennifer R Cochran, James F Spicer, John Maher
Mesothelioma is an incurable cancer for which effective therapies are required. Aberrant MET expression is prevalent in mesothelioma, although targeting using small molecule-based therapeutics has proven disappointing. Chimeric antigen receptors (CARs) couple the HLA-independent binding of a cell surface target to the delivery of a tailored T-cell activating signal. Here, we evaluated the anti-tumor activity of MET re-targeted CAR T-cells against mesothelioma. Using immunohistochemistry, MET was detected in 67% of malignant pleural mesotheliomas, most frequently of epithelioid or biphasic subtype...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29208672/cd271-confers-an-invasive-and-metastatic-phenotype-of-head-and-neck-squamous-cell-carcinoma-through-the-upregulation-of-slug
#17
Man Ki Chung, Young Ho Jung, Joon Kyoo Lee, Soo Youn Cho, Oihana J Murillo-Sauca, Ravindra Uppaluri, June Ho Shin, John B Sunwoo
PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells, and CD271 (NGFR; p75NTR) has been associated with a tumor-initiating cell subpopulation. This study assessed the role of CD271 in modulating metastatic behavior in HNSCC. EXPERIMENTAL DESIGN: CD271 was overexpressed in murine and human oral squamous cell carcinoma cells to assess the impact of CD271 activation on the invasive and metastatic phenotype of these cells, using in vitro and orthotopic in vivo modeling...
December 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29203771/alu-dependent-rna-editing-of-gli1-promotes-malignant-regeneration-in-multiple-myeloma
#18
Elisa Lazzari, Phoebe K Mondala, Nathaniel Delos Santos, Amber C Miller, Gabriel Pineda, Qingfei Jiang, Heather Leu, Shawn A Ali, Anusha-Preethi Ganesan, Christina N Wu, Caitlin Costello, Mark Minden, Raffaella Chiaramonte, A Keith Stewart, Leslie A Crews, Catriona H M Jamieson
Despite novel therapies, relapse of multiple myeloma (MM) is virtually inevitable. Amplification of chromosome 1q, which harbors the inflammation-responsive RNA editase adenosine deaminase acting on RNA (ADAR)1 gene, occurs in 30-50% of MM patients and portends a poor prognosis. Since adenosine-to-inosine RNA editing has recently emerged as a driver of cancer progression, genomic amplification combined with inflammatory cytokine activation of ADAR1 could stimulate MM progression and therapeutic resistance. Here, we report that high ADAR1 RNA expression correlates with reduced patient survival rates in the MMRF CoMMpass data set...
December 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/29203539/novel-and-shared-neoantigen-derived-from-histone-3-variant-h3-3k27m-mutation-for-glioma-t-cell-therapy
#19
Zinal S Chheda, Gary Kohanbash, Kaori Okada, Naznin Jahan, John Sidney, Matteo Pecoraro, Xinbo Yang, Diego A Carrera, Kira M Downey, Shruti Shrivastav, Shuming Liu, Yi Lin, Chetana Lagisetti, Pavlina Chuntova, Payal B Watchmaker, Sabine Mueller, Ian F Pollack, Raja Rajalingam, Angel M Carcaboso, Matthias Mann, Alessandro Sette, K Christopher Garcia, Yafei Hou, Hideho Okada
The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. The majority of diffuse midline gliomas, including more than 70% of DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). From a CD8+ T cell clone established by stimulation of HLA-A2+ CD8+ T cells with synthetic peptide encompassing the H3.3K27M mutation, complementary DNA for T cell receptor (TCR) α- and β-chains were cloned into a retroviral vector...
December 4, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29202831/heterologous-expression-purification-and-function-of-the-extracellular-domain-of-human-rank
#20
Yilei Wei, Yu Zhan, Pengfei Chen, Zhi Liu, Haohao Zhang, Dandan Liu, Jie Zhang, Min Yu, Wei Mo, Jun Zhang, Xiaoren Zhang
BACKGROUND: Receptor activator of NF-κB ligand (RANKL)/RANK signaling essentially functions within the skeletal system, particularly participating in osteoclastogenesis and bone resorption. In addition, this signaling pathway has also been shown to influence tumor progression as well as the development and function of the immune system. Therefore, blocking the interaction between RANKL and RANK is a new therapeutic approach to prevent bone-related diseases and cancer. RESULTS: The coding sequence encoding the extracellular domain of human RANK (RANK-N) was codon optimized for Pichia pastoris and cloned into the pPIC9K vector, and the recombinant plasmid was then transformed into P...
December 4, 2017: BMC Biotechnology
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