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patient derived xenograft cancer

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https://www.readbyqxmd.com/read/28821559/synergy-of-wee1-and-mtor-inhibition-in-mutant-kras-driven-lung-cancers
#1
Josephine Hai, Shengwu Liu, Lauren Bufe, Khanh Do, Ting Chen, Xiaoen Wang, Christine Ng, Shuai Li, Ming-Sound Tsao, Geoffrey I Shapiro, Kwok-Kin Wong
Purpose:KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multi-targeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations. <p>Experimental Design: We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines...
August 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28810913/selinexor-kpt-330-demonstrates-anti-tumor-efficacy-in-preclinical-models-of-triple-negative-breast-cancer
#2
Natalia Paez Arango, Erkan Yuca, Ming Zhao, Kurt W Evans, Stephen Scott, Charissa Kim, Ana Maria Gonzalez-Angulo, Filip Janku, Naoto T Ueno, Debu Tripathy, Argun Akcakanat, Aung Naing, Funda Meric-Bernstam
BACKGROUND: Selinexor (KPT-330) is an oral agent that has been shown to inhibit the nuclear exporter XPO1. Given the pressing need for novel therapies for triple-negative breast cancer (TNBC), we sought to determine the antitumor effects of selinexor in vitro and in vivo. METHODS: Twenty-six breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro. Cell proliferation assays were used to measure the half-maximal inhibitory concentration (IC50) and to test the effects in combination with chemotherapy...
August 15, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28808038/the-phosphatidylinositol-3-kinase-pathway-as-a-potential-therapeutic-target-in-bladder-cancer
#3
Shuxiong Zeng, Yanjun Zhu, Ai-Hong Ma, Weimin Yu, Hongyong Zhang, Tzu-Yin Lin, Wei Shi, Clifford G Tepper, Paul T Henderson, Susan Airhart, Jianming Guo, Chuanliang Xu, Ralph de Vere White, Chong-Xian Pan
PURPOSE: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action and resistant mechanisms of drugs targeting the PI3K pathway. EXPERIMENTAL DESIGN: Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine...
August 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28806950/precision-medicine-approaches-to-lung-adenocarcinoma-with-concomitant-met-and-her2-amplification
#4
Doo-Yi Oh, Kyungsoo Jung, Ji-Young Song, Seokhwi Kim, Sang Shin, Yong-Jun Kwon, Ensel Oh, Woong-Yang Park, Sang Yong Song, Yoon-La Choi
BACKGROUND: Patient-derived xenograft (PDX) models are important tools in precision medicine and for the development of targeted therapies to treat cancer patients. This study aimed to evaluate our precision medicine strategy that integrates genomic profiling and preclinical drug-screening platforms, in order to personalize cancer treatments using PDX models. METHODS: We performed array-comparative genomic hybridization, microarray, and targeted next-generation sequencing analyses, in order to determine the oncogenic driver mutations...
August 10, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28804556/anti-tumor-efficacy-evaluation-of-a-novel-monoclonal-antibody-targeting-neutral-amino-acid-transporter-asct2-using-patient-derived-xenograft-mouse-models-of-gastric-cancer
#5
Noriyuki Kasai, Aya Sasakawa, Kenta Hosomi, Tze Wei Poh, Bernadette Lynn Chua, Wei Peng Yong, Jimmy So, Shing Leng Chan, Richie Soong, Koji Kono, Toshihiko Ishii, Kazuya Yamano
ASC amino acid transporter 2 (ASCT2), also known as solute linked carrier family 1 member A5 (SLC1A5) is a Na+-dependent glutamine/neutral amino acid transporter. ASCT2 acts as a high-affinity transporter of L-glutamine (Gln) and has been reported to be up-regulated in a variety of cancerous tissues including stomach, liver, and kidney. In this study, we evaluated anti-tumor efficacy of a novel anti-ASCT2 humanized monoclonal antibody, KM8094, which has a neutralizing activity against glutamine uptake, as a therapeutic antibody against gastric cancer and explored clinical predictive biomarker candidates by utilizing patient-derived xenograft (PDX) mouse models...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28797031/regulation-of-hypoxia-induced-autophagy-in-glioblastoma-involves-atg9a
#6
Siti Aminah Abdul Rahim, Anne Dirkse, Anais Oudin, Anne Schuster, Jill Bohler, Vanessa Barthelemy, Arnaud Muller, Laurent Vallar, Bassam Janji, Anna Golebiewska, Simone P Niclou
BACKGROUND: Hypoxia is negatively associated with glioblastoma (GBM) patient survival and contributes to tumour resistance. Anti-angiogenic therapy in GBM further increases hypoxia and activates survival pathways. The aim of this study was to determine the role of hypoxia-induced autophagy in GBM. METHODS: Pharmacological inhibition of autophagy was applied in combination with bevacizumab in GBM patient-derived xenografts (PDXs). Sensitivity towards inhibitors was further tested in vitro under normoxia and hypoxia, followed by transcriptomic analysis...
August 10, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28791708/exosomal-dnmt1-mediates-cisplatin-resistance-in-ovarian-cancer
#7
Ya-Lei Cao, Ting Zhuang, Bao-Heng Xing, Na Li, Qin Li
Ovarian cancer is the most common malignancy in women. Owing to late syndromic presentation and lack of efficient early detection, most cases are diagnosed at advanced stages. Surgery and platinum-based chemotherapy are still the standard care currently. However, resistance invoked often compromises the clinical value of the latter. Expression of DNA methyltransferase 1 (DNMT1) was analysed by gene array. Protein was determined by immunoblotting. Exosome was isolated with commercial kit. Cell proliferation was measured by CCK8 method...
August 8, 2017: Cell Biochemistry and Function
https://www.readbyqxmd.com/read/28790197/breast-tumors-educate-the-proteome-of-stromal-tissue-in-an-individualized-but-coordinated-manner
#8
Xuya Wang, Arshag D Mooradian, Petra Erdmann-Gilmore, Qiang Zhang, Rosa Viner, Sherri R Davies, Kuan-Lin Huang, Ryan Bomgarden, Brian A Van Tine, Jieya Shao, Li Ding, Shunqiang Li, Matthew J Ellis, John C Rogers, R Reid Townsend, David Fenyö, Jason M Held
Cancer forms specialized microenvironmental niches that promote local invasion and colonization. Engrafted patient-derived xenografts (PDXs) locally invade and colonize naïve stroma in mice while enabling unambiguous molecular discrimination of human proteins in the tumor from mouse proteins in the microenvironment. To characterize how patient breast tumors form a niche and educate naïve stroma, subcutaneous breast cancer PDXs were globally profiled by species-specific quantitative proteomics. Regulation of PDX stromal proteins by breast tumors was extensive, with 35% of the stromal proteome altered by tumors consistently across different animals and passages...
August 8, 2017: Science Signaling
https://www.readbyqxmd.com/read/28783167/toosendanin-demonstrates-promising-antitumor-efficacy-in-osteosarcoma-by-targeting-stat3
#9
T Zhang, J Li, F Yin, B Lin, Z Wang, J Xu, H Wang, D Zuo, G Wang, Y Hua, Z Cai
Signal transducer and activator of transcription 3(STAT3) is an emerging target for cancer therapy. In this study, we identify Toosendanin (TSN) is an effective inhibitor of STAT3, leading to the impediment of various oncogenic processes in osteosarcoma. TSN selectively inactivates phospho-STAT3 (Tyr-705); subsequent molecular docking and in vitro SPR analysis uncover TSN directly binds to the SH2 domain of STAT3. Consequently, TSN blocks STAT3 dimerization and impairs the complex formation of STAT3 and epidermal growth factor receptor (EGFR)...
August 7, 2017: Oncogene
https://www.readbyqxmd.com/read/28782139/low-doses-of-curcuma-longa-modulates-cell-migration-and-cell-cell-adhesion
#10
Paloma Santos de Campos, Bibiana Franzen Matte, Leonardo Francisco Diel, Luciano Henrique Jesus, Lisiane Bernardi, Alessandro Menna Alves, Pantelis Varvaki Rados, Marcelo Lazzaron Lamers
Cell invasion and metastasis are involved in clinical failures in cancer treatment, and both events require the acquisition of a migratory behavior by tumor cells. Curcumin is a promising natural product with anti-proliferative activity, but its effects on cell migration are still unclear. We evaluated the effects of curcumin on the proliferation, apoptosis, migration, and cell-cell adhesion of keratinocyte, oral squamous cell carcinoma (OSCC), and fibroblast cell lines, as well as in a xenograft model of OSCC...
August 7, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28778085/investigation-of-factors-affecting-the-efficacy-of-3c23k-a-human-monoclonal-antibody-targeting-misiir
#11
Sarah E Gill, Qing Zhang, Gary L Keeney, William A Cliby, S John Weroha
MISIIR is a potential target for ovarian cancer (OC) therapy due to its tissue-specific pattern of expression. 3C23K is a novel therapeutic monoclonal anti-MISIIR antibody designed to recruit effector cells and promote cell death through ADCC (antibody dependent cell-mediated cytotoxicity). Our objective was to determine the tolerability and efficacy of 3C23K in OC patient-derived xenografts (PDX) and to identify factors affecting efficacy. Quantitative RT-PCR, immunohistochemistry (IHC), and flow cytometry were used to categorize MISIIR expression in established PDX models derived from primary OC patients...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28778066/inhibition-of-lsd1-epigenetically-attenuates-oral-cancer-growth-and-metastasis
#12
Saqer F Alsaqer, Mustafa M Tashkandi, Vinay K Kartha, Ya-Ting Yang, Yazeed Alkheriji, Andrew Salama, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti, Manish V Bais
Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase and a member of the amine oxidase (AO) family. LSD1 is a flavin-containing AO that specifically catalyzes the demethylation of mono- and di-methylated histone H3 lysine 4 through an FAD-dependent oxidative reaction. LSD1 is inappropriately upregulated in lung, liver, brain and esophageal cancers, where it promotes cancer initiation, progression, and metastasis. However, unlike other lysine-specific demethylases, the role and specific targets of LSD1 in oral squamous cell carcinoma (OSCC) pathogenesis remain unknown...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28768804/synergistic-action-of-the-mcl-1-inhibitor-s63845-with-current-therapies-in-preclinical-models-of-triple-negative-and-her2-amplified-breast-cancer
#13
Delphine Merino, James R Whittle, François Vaillant, Antonin Serrano, Jia-Nan Gong, Goknur Giner, Ana Leticia Maragno, Maïa Chanrion, Emilie Schneider, Bhupinder Pal, Xiang Li, Grant Dewson, Julius Gräsel, Kevin Liu, Najoua Lalaoui, David Segal, Marco J Herold, David C S Huang, Gordon K Smyth, Olivier Geneste, Guillaume Lessene, Jane E Visvader, Geoffrey J Lindeman
The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer...
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28768734/human-tissue-models-in-cancer-research-looking-beyond-the-mouse
#14
EDITORIAL
Samuel J Jackson, Gareth J Thomas
Mouse models, including patient-derived xenograft mice, are widely used to address questions in cancer research. However, there are documented flaws in these models that can result in the misrepresentation of human tumour biology and limit the suitability of the model for translational research. A coordinated effort to promote the more widespread development and use of 'non-animal human tissue' models could provide a clinically relevant platform for many cancer studies, maximising the opportunities presented by human tissue resources such as biobanks...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28765324/glesatinib-exhibits-antitumor-activity-in-lung-cancer-models-and-patients-harboring-met-exon-14-mutations-and-overcomes-mutation-mediated-resistance-to-type-i-met-inhibitors-in-nonclinical-models
#15
Lars Engstrom, Ruth Aranda, Matthew Lee, Elizabeth A Tovar, Curt Essenburg, Zachary B Madaj, Harrah Chiang, David Briere, Jill Hallin, Pedro P Lopez-Casas, Natalia Banos, Camino Menéndez, Manuel Hidalgo, Vanessa Tassell, Richard Chao, Darya I Chudova, Richard B Lanman, Peter Olson, Lyudmila Bazhenova, Sandip P Patel, Carrie R Graveel, Mizuki Nishino, Geoffrey I Shapiro, Nir Peled, Mark M Awad, Pasi A Janne, James G Christensen
MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations.  We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET Inhibitors.<br /><br />Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28762582/detection-of-homozygous-deletions-in-tumor-suppressor-genes-ranging-from-dozen-to-hundreds-nucleotides-in-cancer-models
#16
Lun-Ching Chang, Suleyman Vural, Dmitriy Sonkin
Tumor suppressor genes can be inactivated by several mechanisms and, in a majority of cases, both alleles need to be affected. One of the mechanisms of inactivation is due to deletions ranging from dozen to hundreds of nucleotides; such deletions are often missed by variant callers. HomDelDetect is a method to detect such homozygous deletions in cancer models, such as cancer cell lines and potentially patient tumor derived xenografts. This method can be applied to partial exome, whole exome, whole genome sequencing, and RNA-seq data...
August 1, 2017: Human Mutation
https://www.readbyqxmd.com/read/28760449/tumor-microenvironment-determines-response-to-a-heat-activated-thermosensitive-liposome-formulation-of-cisplatin-in-cervical-carcinoma
#17
Yannan N Dou, Naz Chaudary, Martin C Chang, Michael Dunne, Huang Huang, David A Jaffray, Michael Milosevic, Christine Allen
Significant heterogeneity in the tumor microenvironment of human cervical cancer patients is known to challenge treatment outcomes in this population. The current standard of care for cervical cancer patients is radiation therapy and concurrent cisplatin (CDDP) chemotherapy. Yet this treatment strategy fails to control loco-regional disease in 10-30% of patients. In order to improve the loco-regional control rate, a thermosensitive liposome formulation of CDDP (HTLC) was developed to increase local concentrations of drug in response to mild hyperthermia (HT)...
July 29, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28754458/terfenadine-combined-with-epirubicin-impedes-the-chemo-resistant-human-non-small-cell-lung-cancer-both-in-vitro-and-in-vivo-through-emt-and-notch-reversal
#18
Li An, Dan-Dan Li, Hai-Xiao Chu, Qiao Zhang, Chang-Li Wang, Yan-Hua Fan, Qi Song, Hong-Da Ma, Fan Feng, Qing-Chun Zhao
The acquired resistance of non-small cell lung cancer (NSCLC) to taxanes eventually leads to the recurrence and metastasis of tumours. Thus, the development of therapeutic strategies based on the mechanisms by which cells acquire resistance to prolong their survival rate in chemotherapy drug treatment failure patients are warranted. In this study, we found that the resistant cells acquired increased migratory and invasive capabilities, and this transformation was correlated with epithelial-mesenchymal transition (EMT) and Notch pathway deregulation in the resistant cells...
July 25, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28753202/targeting-the-cxcr4-cxcl12-axis-in-treating-epithelial-ovarian-cancer
#19
T L Mao, K F Fan, C L Liu
Ovarian carcinoma is the most crucial and difficult target for available therapeutic treatments among gynecological malignancies, and great efforts are required to find an effective solution. Molecular studies showed that the chemokine stromal cell-derived factor (SDF)-1 (also known as CXCL12) and its receptor, CXCR4, are key determinants of tumor initiation, progression, and metastasis in ovarian carcinomas. Hence, it is generally believed that blocking the CXCR4/CXCL12 pathway could serve as a potential therapy for patients with ovarian cancer...
July 28, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28751748/establishment-of-patient-derived-xenografts-as-functional-testing-of-lung-cancer-aggressiveness
#20
Moro Massimo, Bertolini Giulia, Caserini Roberto, Borzi Cristina, Boeri Mattia, Fabbri Alessandra, Leone Giorgia, Gasparini Patrizia, Galeone Carlotta, Pelosi Giuseppe, Roz Luca, Sozzi Gabriella, Pastorino Ugo
Despite many years of research efforts, lung cancer still remains the leading cause of cancer deaths worldwide. Objective of this study was to set up a platform of non-small cell lung cancer patient derived xenografts (PDXs) faithfully representing primary tumour characteristics and offering a unique tool for studying effectiveness of therapies at a preclinical level. We established 38 PDXs with a successful take rate of 39.2%. All models closely mirrored parental tumour characteristics although a selective pressure for solid patterns, vimentin expression and EMT was observed in several models...
July 27, 2017: Scientific Reports
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