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https://www.readbyqxmd.com/read/29245013/combination-cancer-therapy-can-confer-benefit-via-patient-to-patient-variability-without-drug-additivity-or-synergy
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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/29230817/ebv-encoded-mirnas-target-atm-mediated-response-in-nasopharyngeal-carcinoma
#7
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
#8
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
#9
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/29228593/proteasome-inhibitor-bortezomib-enhances-the-effect-of-standard-chemotherapy-in-small-cell-lung-cancer
#10
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/29212525/establishing-and-characterizing-patient-derived-xenografts-using-pre-chemotherapy-percutaneous-biopsy-and-post-chemotherapy-surgical-samples-from-a-prospective-neoadjuvant-breast-cancer-study
#11
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
#12
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
#13
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
#14
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/29202831/heterologous-expression-purification-and-function-of-the-extracellular-domain-of-human-rank
#15
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
https://www.readbyqxmd.com/read/29202777/identification-of-coexistence-of-braf-v600e-mutation-and-ezh2-gain-specifically-in-melanoma-as-a-promising-target-for-combination-therapy
#16
Huan Yu, Meng Ma, Junya Yan, Longwen Xu, Jiayi Yu, Jie Dai, Tianxiao Xu, Huan Tang, Xiaowen Wu, Siming Li, Bin Lian, Lili Mao, Zhihong Chi, Chuanliang Cui, Jun Guo, Yan Kong
BACKGROUND: Coexistence of enhancer of zeste homolog 2 (EZH2) and BRAF gene aberrations has been described in many cancer types. In this study, we aim to explore the coexistence status of BRAF V600E mutation and the copy number variation of EZH2 and explore the potential of this combination as a therapeutic target. METHODS: A total of 138 cases of melanoma samples harboring BRAF V600E mutation were included, and EZH2 copy numbers were examined by QuantiGenePlex DNA Assays...
December 4, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29201215/contrast-enhanced-computerized-tomography-combined-with-a-targeted-nanoparticle-contrast-agent-for-screening-for-early-phase-non-small-cell-lung-cancer
#17
Ninglu Yuan, Xiaohe Zhang, Yonghui Cao, Xiaojie Jiang, Si Zhao, Yingying Feng, Yimeng Fan, Zhitao Lu, Hongmei Gao
Non-small cell lung cancer (NSCLC) is a major cause of morbidity and mortality, and patients with NSCLC are frequently diagnosed at an advanced stage. This is primarily due to a lack of advanced and sensitive protocols for the detection of early stage NSCLC. Therefore, methods for the accurate diagnosis of early stage NSCLC are urgently required to improve survival rates. The present study investigated the use of contrast-enhanced computerized tomography (CECT) combined with a targeted nanoparticle contrast agent (TNCA) to diagnose early-stage NSCLC in a mice xenograft model...
November 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29197033/establishment-and-proteomic-characterization-of-patient-derived-clear-cell-sarcoma-xenografts-and-cell-lines
#18
Marimu Sakumoto, Rieko Oyama, Mami Takahashi, Yoko Takai, Fusako Kito, Kumiko Shiozawa, Zhiwei Qiao, Makoto Endo, Akihiko Yoshida, Akira Kawai, Tadashi Kondo
Clear cell sarcoma (CCS) is an aggressive mesenchymal malignancy characterized by the unique chimeric EWS-ATF1 fusion gene. Patient-derived cancer models are essential tools for the understanding of tumorigenesis and the development of anti-cancer drugs; however, only a limited number of CCS cell lines exist. The objective of this study was to establish patient-derived CCS models. We established patient-derived CCS models from a 43-yr-old female patient. We prepared the patient-derived xenografts (PDXs) from tumor tissues obtained through biopsy or surgery and isolated stable cell lines from PDXs and the original tumor tissue...
December 1, 2017: In Vitro Cellular & Developmental Biology. Animal
https://www.readbyqxmd.com/read/29196706/maldi-mass-spectrometry-imaging-of-erlotinib-administered-in-combination-with-bevacizumab-in-xenograft-mice-bearing-b901l-egfr-mutated-nsclc-cells
#19
Masanobu Nishidate, Kaname Yamamoto, Chinami Masuda, Hiroaki Aikawa, Mitsuhiro Hayashi, Takehiko Kawanishi, Akinobu Hamada
Combination therapy of erlotinib plus bevacizumab improves progression-free survival of patients with epidermal growth factor receptor-mutated (EGFR-mutated) advanced non-small-cell lung cancer (NSCLC) compared with erlotinib alone. Although improved delivery and distribution of erlotinib to tumours as a result of the normalization of microvessels by bevacizumab is thought to be one of the underlying mechanisms, there is insufficient supporting evidence. B901L cells derived from EGFR-mutated NSCLC were subcutaneously implanted into mice, and mice were treated with bevacizumab or human IgG followed by treatment with erlotinib...
December 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29192179/cmscaller-an-r-package-for-consensus-molecular-subtyping-of-colorectal-cancer-pre-clinical-models
#20
Peter W Eide, Jarle Bruun, Ragnhild A Lothe, Anita Sveen
Colorectal cancers (CRCs) can be divided into four gene expression-based biologically distinct consensus molecular subtypes (CMS). This classification provides a potential framework for stratified treatment, but to identify novel CMS-drug associations, translation of the subtypes to pre-clinical models is essential. The currently available classifier is dependent on gene expression signals from the immune and stromal compartments of tumors and fails to identify the poor-prognostic CMS4-mesenchymal group in immortalized cell lines, patient-derived organoids and xenografts...
November 30, 2017: Scientific Reports
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