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Patient derived xenograft PDX

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https://www.readbyqxmd.com/read/27917934/c-met-as-a-potential-therapeutic-target-in-ovarian-clear-cell-carcinoma
#1
Ha-Jeong Kim, Aera Yoon, Ji-Yoon Ryu, Young-Jae Cho, Jung-Joo Choi, Sang Yong Song, Heejin Bang, Ji Soo Lee, William Chi Cho, Chel Hun Choi, Jeong-Won Lee, Byoung-Gie Kim, Duk-Soo Bae
In this study, we investigated the therapeutic effects of c-MET inhibition in ovarian clear cell carcinoma (OCCC). Expression levels of c-MET in the epithelial ovarian cancers (EOCs) and normal ovarian tissues were evaluated using real-time PCR. To test the effects of c-MET inhibitors in OCCC cell lines, we performed MTT and apoptosis assays. We used Western blots to evaluate the expression of c-MET and its down-stream pathway. In vivo experiments were performed to test the effects of c-MET inhibitor on tumor growth in orthotopic mouse xenografts of OCCC cell line RMG1 and a patient-derived tumor xenograft (PDX) model of OCCC...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27902465/gene-and-microrna-modulation-upon-trabectedin-treatment-in-a-human-intrahepatic-cholangiocarcinoma-paired-patient-derived-xenograft-and-cell-line
#2
Caterina Peraldo Neia, Giuliana Cavalloni, Giovanna Chiorino, Paola Ostano, Massimo Aglietta, Francesco Leone
Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. Trabectedin has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of trabectedin at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of trabectedin were explored in the in vitro model. In vitro, trabectedin inhibited genes involved in protein modification, neurogenesis, migration, and motility; it induced the expression of genes involved in keratinization, tissues development, and apoptotic processes...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27888804/niclosamide-and-its-analogs-are-potent-inhibitors-of-wnt-%C3%AE-catenin-mtor-and-stat3-signaling-in-ovarian-cancer
#3
Rebecca C Arend, Angelina I Londoño-Joshi, Abhishek Gangrade, Ashwini A Katre, Chandrika Kurpad, Yonghe Li, Rajeev S Samant, Pui-Kai Li, Charles N Landen, Eddy S Yang, Bertha Hidalgo, Ronald D Alvarez, J Michael Straughn, Andres Forero, Donald J Buchsbaum
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of cancer stem cells (CSCs) include Wnt/β-catenin, mTOR, and STAT3. The major objective of our study was to investigate the treatment of ovarian cancer with targeted agents that inhibit these three pathways...
November 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27880910/cdk12-inhibition-reverses-de-novo-and-acquired-parp-inhibitor-resistance-in-brca-wild-type-and-mutated-models-of-triple-negative-breast-cancer
#4
Shawn F Johnson, Cristina Cruz, Ann Katrin Greifenberg, Sofia Dust, Daniel G Stover, David Chi, Benjamin Primack, Shiliang Cao, Andrea J Bernhardy, Rhiannon Coulson, Jean-Bernard Lazaro, Bose Kochupurakkal, Heather Sun, Christine Unitt, Lisa A Moreau, Kristopher A Sarosiek, Maurizio Scaltriti, Dejan Juric, José Baselga, Andrea L Richardson, Scott J Rodig, Alan D D'Andrea, Judith Balmaña, Neil Johnson, Matthias Geyer, Violeta Serra, Elgene Lim, Geoffrey I Shapiro
Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27835884/combination-of-cox-2-expression-and-pik3ca-mutation-as-prognostic-and-predictive-markers-for-celecoxib-treatment-in-breast-cancer
#5
Sandrine Tury, Véronique Becette, Franck Assayag, Sophie Vacher, Camille Benoist, Maud Kamal, Elisabetta Marangoni, Ivan Bièche, Florence Lerebours, Céline Callens
COX-2 expression level and prognostic value are still a matter of debate in breast cancer (BC). We addressed these points in the context of PIK3CA mutational status. Based on an interesting study of aspirin efficacy in colorectal cancer, we hypothesized that celecoxib antitumoral activity may be restricted to PIK3CA mutated BC.COX-2 mRNA expression was analyzed in 446 BC samples and in 61 BC patient-derived xenografts (PDX) using quantitative RT-PCR. The prognostic impact of COX-2 expression level was assessed independently and according to PIK3CA mutational status in our cohort and in a validation set of 817 BC...
November 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27823983/genomic-profiling-is-predictive-of-response-to-cisplatin-treatment-but-not-to-pi3k-inhibition-in-bladder-cancer-patient-derived-xenografts
#6
Lei Wei, Sreenivasulu Chintala, Eric Ciamporcero, Swathi Ramakrishnan, May Elbanna, Jianmin Wang, Qiang Hu, Sean T Glenn, Mitsuko Murakami, Lu Liu, Eduardo Cortes Gomez, Yuchen Sun, Jacob Conroy, Kiersten Marie Miles, Kullappan Malathi, Sudha Ramaiah, Anand Anbarasu, Anna Woloszynska-Read, Candace S Johnson, Jeffrey Conroy, Song Liu, Carl D Morrison, Roberto Pili
PURPOSE: Effective systemic therapeutic options are limited for bladder cancer. In this preclinical study we tested whether bladder cancer gene alterations may be predictive of treatment response. EXPERIMENTAL DESIGN: We performed genomic profiling of two bladder cancer patient derived tumor xenografts (PDX). We optimized the exome sequence analysis method to overcome the mouse genome interference. RESULTS: We identified a number of somatic mutations, mostly shared by the primary tumors and PDX...
November 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/27799065/a-case-study-of-an-integrative-genomic-and-experimental-therapeutic-approach-for-rare-tumors-identification-of-vulnerabilities-in-a-pediatric-poorly-differentiated-carcinoma
#7
Filemon S Dela Cruz, Daniel Diolaiti, Andrew T Turk, Allison R Rainey, Alberto Ambesi-Impiombato, Stuart J Andrews, Mahesh M Mansukhani, Peter L Nagy, Mariano J Alvarez, Andrea Califano, Farhad Forouhar, Beata Modzelewski, Chelsey M Mitchell, Darrell J Yamashiro, Lianna J Marks, Julia L Glade Bender, Andrew L Kung
BACKGROUND: Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities...
October 31, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27796962/patient-derived-xenografts-of-breast-cancer
#8
Damir Varešlija, Sinead Cocchiglia, Christopher Byrne, Leonie Young
With the advancement of translational research, particularly in the field of cancer, it is now imperative to have models which more clearly reflect patient heterogeneity. Patient derived xenograft (PDX) models, which involve the orthotopic implantation of breast tumors into immune-compromised mice, recapitulate the native tumor biology. Despite the considerable challenges that establishing PDX models present, they are the ultimate model to study tumorigenesis of refractory disease and for assessing the efficacy of new pharmaceutical compounds...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27796944/steroid-hormone-receptor-positive-breast-cancer-patient-derived-xenografts
#9
Shawna B Matthews, Carol A Sartorius
The vast majority of breast cancers are positive for estrogen receptor (ER) and depend on estrogens for growth. These tumors are treated with a variety of ER-targeted endocrine therapies, although eventual resistance remains a major clinical problem. Other steroid hormone receptors such as progesterone receptor (PR) and androgen receptor (AR) are emerging as additional prospective targets in breast cancer. The fundamental mechanism of action of these steroid receptors in gene regulation has been defined mainly by several breast cancer cell lines that were established in the late 1970s...
October 28, 2016: Hormones & Cancer
https://www.readbyqxmd.com/read/27793847/dna-repair-capacity-in-multiple-pathways-predicts-chemoresistance-in-glioblastoma-multiforme
#10
Zachary D Nagel, Gaspar J Kitange, Shiv K Gupta, Brian A Joughin, Isaac A Chaim, Patrizia Mazzucato, Douglas A Lauffenburger, Jann N Sarkaria, Leona D Samson
Cancer cells can resist the effects of DNA-damaging therapeutic agents via utilization of DNA repair pathways, suggesting that DNA repair capacity (DRC) measurements in cancer cells could be used to identify patients most likely to respond to treatment. However, the limitations of available technologies have so far precluded adoption of this approach in the clinic. We recently developed fluorescence-based multiplexed host cell reactivation (FM-HCR) assays to measure DRC in multiple pathways. Here we apply a mathematical model that uses DRC in multiple pathways to predict cellular resistance to killing by DNA-damaging agents...
October 28, 2016: Cancer Research
https://www.readbyqxmd.com/read/27791181/targeted-molecular-genetic-imaging-and-ligand-directed-therapy-in-aggressive-variant-prostate-cancer
#11
Fortunato Ferrara, Daniela I Staquicini, Wouter H P Driessen, Sara D'Angelo, Andrey S Dobroff, Marc Barry, Lesley C Lomo, Fernanda I Staquicini, Marina Cardó-Vila, Suren Soghomonyan, Mian M Alauddin, Leo G Flores, Marco A Arap, Richard C Lauer, Paul Mathew, Eleni Efstathiou, Ana M Aparicio, Patricia Troncoso, Nora M Navone, Christopher J Logothetis, Serena Marchiò, Juri G Gelovani, Richard L Sidman, Renata Pasqualini, Wadih Arap
Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients...
October 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27784882/induction-of-patient-derived-xenograft-formation-and-clinical-significance-of-programmed-cell-death-ligand-1-pd-l1-in-lung-cancer-patients
#12
Yuanyuan Ma, Panpan Zhang, Guo An, Xiaolong Zhang, Liyi Zhang, Jiahui Si, Jianzhi Zhang, Yue Yang
BACKGROUND The immune checkpoint of programmed cell death ligand 1 (PD-L1) commonly expressed in solid cancers, and the blockade of this molecule show promising results in advanced cancers, including lung cancer. The relevance of PD-L1 to patient-derived xenograft (PDX) formation and clinicopathological characteristics in early stage lung cancer have not been fully elucidated. MATERIAL AND METHODS Cell counting kit-8 and flow cytometry were carried out to examine proliferation and apoptosis in PC9 and H520 cells transfected with siRNAs...
October 27, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/27780858/5t4-targeted-therapy-ablates-cancer-stem-cells-and-prevents-recurrence-of-head-and-neck-squamous-cell-carcinoma
#13
Samuel Kerk, Kelsey Finkel, Alexander T Pearson, Kristy Warner, Felipe Nor, Zhaocheng Zhang, Vivian P Wagner, Pablo A Vargas, Max S Wicha, Elaine Hurt, Robert E Hollingsworth, David A Tice, Jacques E Nor
PURPOSE: Loco-regional recurrence is a frequent treatment outcome for patients with advanced head and neck squamous cell carcinoma (HNSCC). Emerging evidence suggests that tumor recurrence is mediated by a small subpopulation of uniquely tumorigenic cells, i.e. cancer stem cells (CSC), that are resistant to conventional chemotherapy, endowed with self-renewal and multipotency. EXPERIMENTAL DESIGN: Here, we evaluated the efficacy of MEDI0641, a novel antibody-drug conjugate targeted to 5T4 and carrying a DNA-damaging "payload" (pyrrolobenzodiazepine) in preclinical models of HNSCC...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27777285/cabozantinib-is-active-against-human-gastrointestinal-stromal-tumor-xenografts-carrying-different-kit-mutations
#14
Yemarshet K Gebreyohannes, Patrick Schöffski, Thomas Van Looy, Jasmien Wellens, Lise Vreys, Jasmien Cornillie, Ulla Vanleeuw, Dana T Aftab, Maria Debiec-Rychter, Raf Sciot, Agnieszka Wozniak
In the majority of gastrointestinal stromal tumors (GIST), oncogenic signaling is driven by KIT mutations. Advanced GIST is treated with tyrosine kinase inhibitors (TKI) such as imatinib. Acquired resistance to TKI is mainly caused by secondary KIT mutations, but can also be attributed to a switch of KIT dependency to another receptor tyrosine kinase (RTK). We tested the efficacy of cabozantinib, a novel TKI targeting KIT, MET, AXL, and vascular endothelial growth factor receptors (VEGFR), in patient-derived xenograft (PDX) models of GIST, carrying different KIT mutations...
December 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27775705/pim1-kinase-inhibition-as-a-targeted-therapy-against-triple-negative-breast-tumors-with-elevated-myc-expression
#15
Dai Horiuchi, Roman Camarda, Alicia Y Zhou, Christina Yau, Olga Momcilovic, Sanjeev Balakrishnan, Alexandra N Corella, Henok Eyob, Kai Kessenbrock, Devon A Lawson, Lindsey A Marsh, Brittany N Anderton, Julia Rohrberg, Ratika Kunder, Alexey V Bazarov, Paul Yaswen, Michael T McManus, Hope S Rugo, Zena Werb, Andrei Goga
Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors...
November 2016: Nature Medicine
https://www.readbyqxmd.com/read/27775025/basal-tumor-cell-isolation-and-patient-derived-xenograft-engraftment-identify-high-risk-clinical-bladder-cancers
#16
K B Skowron, S P Pitroda, J P Namm, O Balogun, M A Beckett, M L Zenner, O Fayanju, X Huang, C Fernandez, W Zheng, G Qiao, R Chin, S J Kron, N N Khodarev, M C Posner, G D Steinberg, R R Weichselbaum
Strategies to identify tumors at highest risk for treatment failure are currently under investigation for patients with bladder cancer. We demonstrate that flow cytometric detection of poorly differentiated basal tumor cells (BTCs), as defined by the co-expression of CD90, CD44 and CD49f, directly from patients with early stage tumors (T1-T2 and N0) and patient-derived xenograft (PDX) engraftment in locally advanced tumors (T3-T4 or N+) predict poor prognosis in patients with bladder cancer. Comparative transcriptomic analysis of bladder tumor cells isolated from PDXs indicates unique patterns of gene expression during bladder tumor cell differentiation...
October 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27771609/efficacy-of-nedd8-pathway-inhibition-in-preclinical-models-of-poorly-differentiated-clinically-aggressive-colorectal-cancer
#17
Gabriele Picco, Consalvo Petti, Francesco Sassi, Katia Grillone, Giorgia Migliardi, Teresa Rossi, Claudio Isella, Federica Di Nicolantonio, Ivana Sarotto, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico
BACKGROUND: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing. METHODS: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry...
February 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27765934/patient-derived-mouse-models-of-cancer-need-to-be-orthotopic-in-order-to-evaluate-targeted-anti-metastatic-therapy
#18
Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Nan Zhang, Takashi Murakami, Takashi Chishima, Kuniya Tanaka, Yasushi Ichikawa, Michael Bouvet, Itaru Endo, Robert M Hoffman
Patient-derived xenograft (PDX) mouse models of cancer are emerging as an important component of personalized precision cancer therapy. However, most models currently offered to patients contain their tumors subcutaneously-transplanted in immunodeficient mice, which rarely metastasize. In contrast, orthotopic-transplant patient-derived models, termed patient-derived orthotopic xenografts (PDOX), usually metastasize as in the patient. We have demonstrated in the present report why orthotopic models are so important for the patient, since primary and metastatic tumors developed in an orthotopic model can have differential chemosensitivity, not detectable in standard subcutaneous tumor models...
September 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/27765906/targeted-ngs-array-cgh-and-patient-derived-tumor-xenografts-for-precision-medicine-in-advanced-breast-cancer-a-single-center-prospective-study
#19
Anthony Gonçalves, François Bertucci, Arnaud Guille, Severine Garnier, José Adelaide, Nadine Carbuccia, Oliver Cabaud, Pascal Finetti, Serge Brunelle, Gilles Piana, Jeanne Tomassin-Piana, Maria Paciencia, Eric Lambaudie, Cornel Popovici, Renaud Sabatier, Carole Tarpin, Magali Provansal, Jean-Marc Extra, François Eisinger, Hagay Sobol, Patrice Viens, Marc Lopez, Christophe Ginestier, Emmanuelle Charafe-Jauffret, Max Chaffanet, Daniel Birnbaum
BACKGROUND: Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient-derived tumor xenografts (PDX) could be obtained in this population. RESULTS: Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%)...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27765850/reactivation-of-p53-by-mdm2-inhibitor-mi-77301-for-the-treatment-of-endocrine-resistant-breast-cancer
#20
Jianfeng Lu, Donna McEachern, Shunqiang Li, Matthew J Ellis, Shaomeng Wang
Endocrine therapy has been highly effective for the treatment of estrogen receptor-positive breast cancer, but endocrine resistance develops in a significant proportion of patients. In an effort to develop novel therapeutic strategies for the treatment of endocrine-resistant breast cancer, we have evaluated a potent and specific MDM2-p53 interaction inhibitor, MI-77301, which has been advanced into clinical development, for its therapeutic potential and mechanism of action in vitro and in vivo in WHIM9 and WHIM18 patient-derived xenograft (PDX) models...
December 2016: Molecular Cancer Therapeutics
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