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Patient derived xenograft PDX

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https://www.readbyqxmd.com/read/28104906/interrogating-open-issues-in-cancer-precision-medicine-with-patient-derived-xenografts
#1
Annette T Byrne, Denis G Alférez, Frédéric Amant, Daniela Annibali, Joaquín Arribas, Andrew V Biankin, Alejandra Bruna, Eva Budinská, Carlos Caldas, David K Chang, Robert B Clarke, Hans Clevers, George Coukos, Virginie Dangles-Marie, S Gail Eckhardt, Eva Gonzalez-Suarez, Els Hermans, Manuel Hidalgo, Monika A Jarzabek, Steven de Jong, Jos Jonkers, Kristel Kemper, Luisa Lanfrancone, Gunhild Mari Mælandsmo, Elisabetta Marangoni, Jean-Christophe Marine, Enzo Medico, Jens Henrik Norum, Héctor G Palmer, Daniel S Peeper, Pier Giuseppe Pelicci, Alejandro Piris-Gimenez, Sergio Roman-Roman, Oscar M Rueda, Joan Seoane, Violeta Serra, Laura Soucek, Dominique Vanhecke, Alberto Villanueva, Emilie Vinolo, Andrea Bertotti, Livio Trusolino
Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions...
January 20, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28097235/a-patient-derived-xenograft-platform-to-study-brca-deficient-ovarian-cancers
#2
Erin George, Hyoung Kim, Clemens Krepler, Brandon Wenz, Mehran Makvandi, Janos L Tanyi, Eric Brown, Rugang Zhang, Patricia Brafford, Stephanie Jean, Robert H Mach, Yiling Lu, Gordon B Mills, Meenhard Herlyn, Mark Morgan, Xiaochen Zhang, Robert Soslow, Ronny Drapkin, Neil Johnson, Ying Zheng, George Cotsarelis, Katherine L Nathanson, Fiona Simpkins
Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28073890/pancreatic-cancer-cell-lines-as-patient-derived-avatars-genetic-characterisation-and-functional-utility
#3
Erik S Knudsen, Uthra Balaji, Brian Mannakee, Paris Vail, Cody Eslinger, Christopher Moxom, John Mansour, Agnieszka K Witkiewicz
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease with the worst survival rate of common solid tumours. Preclinical models that accurately reflect the genetic and biological diversity of PDAC will be important for delineating features of tumour biology and therapeutic vulnerabilities. DESIGN: 27 primary PDAC tumours were employed for genetic analysis and development of tumour models. Tumour tissue was used for derivation of xenografts and cell lines...
January 10, 2017: Gut
https://www.readbyqxmd.com/read/28073843/active-estrogen-receptor-alpha-signaling-in-ovarian-cancer-models-and-clinical-specimens
#4
Courtney L Andersen, Matthew J Sikora, Michelle M Boisen, Tianzhou Ma, Alec Christie, George Tseng, Yong Seok Park, Soumya Luthra, Uma Chandran, Paul Haluska, Gina Mantia-Smaldone, Kunle Odunsi, Karen McLean, Adrian V Lee, Esther Elishaev, Robert P Edwards, Steffi Oesterreich
PURPOSE: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha in ~80% of HGSOC and some small but promising clinical trials of endocrine therapy, estrogen receptor-alpha has been understudied as a target in this disease. We sought to identify hormone-responsive, estrogen receptor-alpha-dependent HGSOC. EXPERIMENTAL DESIGN: We characterized endocrine response in HGSOC cells across culture conditions (2-D, 3-D, forced suspension) and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28052650/patient-derived-xenograft-models-of-epithelial-ovarian-cancer-for-preclinical-studies
#5
Eun Jin Heo, Young Jae Cho, William Chi Cho, Ji Eun Hong, Hye-Kyung Jeon, Doo-Yi Oh, Yoon-La Choi, Sang Yong Song, Jung-Joo Choi, Duk-Soo Bae, Yoo-Young Lee, Chel Hun Choi, Tae-Joong Kim, Woong-Yang Park, Byoung-Gie Kim, Jeong-Won Lee
Purpose: Patient-derived tumor xenografts (PDXs) can provide more reliable information about tumor biology than cell line models. We developed PDXs for epithelial ovarian cancer (EOC) that have histopathologic and genetic similarities to the primary patient tissues and evaluated their potential for use as a platform for translational EOC research. Materials and Methods: We successfully established PDXs by subrenal capsule implantation of primary EOC tissues into female BALB/C-nude mice...
January 4, 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
https://www.readbyqxmd.com/read/28042317/cd54-notch1-axis-controls-tumor-initiation-and-cancer-stem-cell-functions-in-human-prostate-cancer
#6
Chong Li, Shengwu Liu, Ruping Yan, Ning Han, Kwok-Kin Wong, Lei Li
Cancer stem cells (CSCs) are considered one of the key contributors to chemoresistance and tumor recurrence. Therefore, the precise identification of reliable CSC markers and clarification of the intracellular signaling involved in CSCs remains a great challenge in fields relating to cancer biology. Here, we implemented a novel chemoresistant prostate cancer patient-derived xenograft (PDX) model in NOD/SCID mice and identified CD54 as a candidate gene among the most highly enriched gene expression profiles in prostate tumors exposed to chronic cisplatin administration...
2017: Theranostics
https://www.readbyqxmd.com/read/28039356/immunophenotyping-and-transcriptomic-outcomes-in-pdx-derived-tnbc-tissue
#7
Eileen Snowden, Warren Porter, Friedrich Hahn, Mitchell Ferguson, Frances Tong, Joel S Parker, Aaron Middlebrook, Smita Ghanekar, W Shannon Dillmore, Rainer Blaesius
: Cancer tissue functions as an ecosystem of a diverse set of cells that interact in a complex tumor microenvironment (TME). Genomic tools applied to biopsies in bulk fail to account for this tumor heterogeneity while single cell imaging methods limit the number of cells which can be assessed or are very resource intensive. The current study presents methods based on flow cytometric analysis and cell sorting using known cell surface markers (eg, CD184, CD24, CD90) to identify and interrogate distinct groups of cells in triple-negative breast cancer (TNBC) clinical biopsy specimens from patient-derived xenograft (PDX) models...
December 30, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28025748/patient-derived-xenograft-pdx-models-in-basic-and-translational-breast-cancer-research
#8
Lacey E Dobrolecki, Susie D Airhart, Denis G Alferez, Samuel Aparicio, Fariba Behbod, Mohamed Bentires-Alj, Cathrin Brisken, Carol J Bult, Shirong Cai, Robert B Clarke, Heidi Dowst, Matthew J Ellis, Eva Gonzalez-Suarez, Richard D Iggo, Peter Kabos, Shunqiang Li, Geoffrey J Lindeman, Elisabetta Marangoni, Aaron McCoy, Funda Meric-Bernstam, Helen Piwnica-Worms, Marie-France Poupon, Jorge Reis-Filho, Carol A Sartorius, Valentina Scabia, George Sflomos, Yizheng Tu, François Vaillant, Jane E Visvader, Alana Welm, Max S Wicha, Michael T Lewis
Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC))...
December 27, 2016: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28024726/defining-the-boundaries-and-expanding-the-utility-of-head-and-neck-cancer-patient-derived-xenografts
#9
Adam D Swick, Andrew P Stein, Timothy M McCulloch, Gregory K Hartig, Irene M Ong, Emmanuel Sampene, Prashanth J Prabakaran, Cheng Z Liu, Randall J Kimple
BACKGROUND: Patient derived xenografts (PDXs) represent an essential tool in oncologic research, and we sought to further expand our repertoire of head and neck squamous cell carcinoma (HNSCC) while determining potential boundaries for this system. METHODS: We consented new patients for PDX development and determined if a 24-h time delay from tumor excision to xenograft implantation affected PDX establishment. We developed a tissue microarray (TMA) from formalin fixed, paraffin embedded PDXs and their subsequent passages and carried out quantitative immunohistochemistry for EGFR, pEGFR, pAkt, pERK and ERCC1...
January 2017: Oral Oncology
https://www.readbyqxmd.com/read/27999790/tumor-take-rate-optimization-for-colorectal-carcinoma-patient-derived-xenograft-models
#10
Michael Gock, Florian Kühn, Christina Susanne Mullins, Mathias Krohn, Friedrich Prall, Ernst Klar, Michael Linnebacher
Background. For development of individualized treatment on a routine basis, transfer of patients' tumor tissue in a xenograft model (i.e., generation of patient-derived xenografts (PDX)) is desirable for molecular, biochemical, or functional analyses. Drawbacks are dissatisfactory tumor take rates, the necessity of fast tumor tissue processing, and extensive logistics demanding teamwork of surgeons, pathologists, and laboratory researchers. Methods. The take rates of ten colorectal cancer (CRC) tissue samples in immunodeficient mice were compared after direct cryopreservation and after a 24 h cooling period at 4°C prior to cryopreservation...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27993965/targeting-the-atr-chk1-axis-with-parp-inhibition-results-in-tumor-regression-in-brca-mutant-ovarian-cancer-models
#11
Hyoung Kim, Erin George, Ryan L Ragland, Stavros Rafail, Rugang Zhang, Clemens Krepler, Mark Morgan, Meenhard Herlyn, Eric J Brown, Fiona Simpkins
PURPOSE: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression. EXPERIMENTAL DESIGN: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776) or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell-cycle, genome instability and apoptosis were evaluated in BRCA1/2MUT HGSOC cells...
December 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27986750/human-papillomavirus-regulates-her3-expression-in-head-and-neck-cancer-implications-for-targeted-her3-therapy-in-hpv-patients
#12
Toni M Brand, Stefan Hartmann, Neil E Bhola, Noah D Peyser, Hua Li, Yan Zeng, Erin Isaacson Wechsler, Max V Ranall, Sourav Bandyopadhyay, Umamaheswar Duvvuri, Theresa M LaVallee, Richard C K Jordan, Daniel E Johnson, Jennifer R Grandis
PURPOSE: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of HNSCCs, where viral expression of the E6 and E7 oncoproteins are necessary for tumor growth and maintenance. Although patients with HPV(+) tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV(+) vs. HPV(-) tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide 3-kinase (PI3K) in HPV(+) tumors...
December 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27982543/in-vivo-bioluminescence-imaging-using-orthotopic-xenografts-towards-patient-s-derived-xenograft-medulloblastoma-models
#13
Fatemeh Asadzadeh, Veronica Ferrucci, Pasqualino DE Antonellis, Massimo Zollo
BACKGROUND: Medulloblastoma is a cerebellar neoplasia of the central nervous system. Four molecular subgrups have been identified (MBWNT, MBSHH, MBgroup3 and MBgroup4) with distinct genetics and clinical outcome. Among these, MBgroup3-4 are highly metastatic with the worst prognosis. The current standard therapy includes surgery, radiation and chemotherapy. Thus, specific treatments adapted to cure those different molecular subgroups are needed. The use of orthotopic xenograft models, together with the non-invasive in vivo biolumiscence imaging (BLI) technology, is emerging during preclinical studies to test novel therapeutics for medulloblastoma treatment...
March 2017: Quarterly Journal of Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/27980108/dual-hdac-and-pi3k-inhibitor-cudc-907-downregulates-myc-and-suppresses-growth-of-myc-dependent-cancers
#14
Kaiming Sun, Ruzanna Atoyan, Mylissa A Borek, Steven DellaRocca, Maria Elena S Samson, Anna W Ma, Guang-Xin Xu, Troy Patterson, David P Tuck, Jaye L Viner, Ali Fattaey, Jing Wang
Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDACs) and phosphoinositide 3-kinases (PI3Ks), can reduce MYC protein levels and suppress the growth of MYC-driven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear...
December 15, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27941872/er-stress-protein-agr2-precedes-and-is-involved-in-the-regulation-of-pancreatic-cancer-initiation
#15
L Dumartin, W Alrawashdeh, S M Trabulo, T P Radon, K Steiger, R M Feakins, M P di Magliano, C Heeschen, I Esposito, N R Lemoine, T Crnogorac-Jurcevic
The mechanisms of initiation of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. In the present study, we analysed the role of anterior gradient-2 (AGR2) in the earliest stages of pancreatic neoplasia. Immunohistochemical analysis of chronic pancreatitis (CP) and peritumoral areas in PDAC tissues showed that AGR2 was present in tubular complexes (TC) and early pancreatic intraepithelial neoplasia (PanINs). Moreover, AGR2 was also found in discrete subpopulations of non-transformed cells neighbouring these pre-neoplastic lesions...
December 12, 2016: Oncogene
https://www.readbyqxmd.com/read/27941840/enhancing-radiosensitization-in-ephb4-receptor-expressing-head-and-neck-squamous-cell-carcinomas
#16
Shilpa Bhatia, Kellen Hirsch, Jaspreet Sharma, Ayman Oweida, Anastacia Griego, Stephen Keysar, Antonio Jimeno, David Raben, Valery Krasnoperov, Parkash S Gill, Elena B Pasquale, Xiao-Jing Wang, Sana D Karam
Members of the Eph family of receptor tyrosine kinases have been implicated in a wide array of human cancers. The EphB4 receptor is ubiquitously expressed in head and neck squamous cell carcinoma (HNSCC) and has been shown to impart tumorigenic and invasive characteristics to these cancers. In this study, we investigated whether EphB4 receptor targeting can enhance the radiosensitization of HNSCC. Our data show that EphB4 is expressed at high to moderate levels in HNSCC cell lines and patient-derived xenograft (PDX) tumors...
December 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27935045/patient-derived-xenografts-of-gastrointestinal-cancers-are-susceptible-to-rapid-and-delayed-b-lymphoproliferation
#17
Sebastian M Dieter, Klara M Giessler, Mark Kriegsmann, Taronish D Dubash, Lino Möhrmann, Erik R Schulz, Christine Siegl, Sarah Weber, Hendrik Strakerjahn, Ava Oberlack, Ulrike Heger, Jianpeng Gao, Eva-Maria Hartinger, Felix Oppel, Christopher M Hoffmann, Nati Ha, Benedikt Brors, Felix Lasitschka, Alexis Ulrich, Oliver Strobel, Manfred Schmidt, Christof von Kalle, Martin Schneider, Wilko Weichert, K Roland Ehrenberg, Hanno Glimm, Claudia R Ball
Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl) /SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro...
December 9, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27929464/labeling-of-breast-cancer-patient-derived-xenografts-with-traceable-reporters-for-tumor-growth-and-metastasis-studies
#18
Colton Hanna, Letty Kwok, Jessica Finlay-Schultz, Carol A Sartorius, Diana M Cittelly
The use of preclinical models to study tumor biology and response to treatment is central to cancer research. Long-established human cell lines, and many transgenic mouse models, often fail to recapitulate the key aspects of human malignancies. Thus, alternative models that better represent the heterogeneity of patients' tumors and their metastases are being developed. Patient-derived xenograft (PDX) models in which surgically resected tumor samples are engrafted into immunocompromised mice have become an attractive alternative as they can be transplanted through multiple generations,and more efficiently reflect tumor heterogeneity than xenografts derived from human cancer cell lines...
November 30, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27923843/therapeutic-activity-of-anti-axl-antibody-against-triple-negative-breast-cancer-patient-derived-xenografts-and-metastasis
#19
Wilhem Leconet, Myriam Chentouf, Stanislas Du Manoir, Clément Chevalier, Audrey Sirevnt, Imade Aït-Arsa, Muriel Busson, Marta Jarlier, Nina Radosevic-Robin, Charles G Theillet, Dany Chalbos, Jean-Max Pasquet, André Pèlegrin, Christel Larbouret, Bruno Robert
PURPOSE: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: We evaluate the anti-tumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration and invasion signaling pathways...
December 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27917934/c-met-as-a-potential-therapeutic-target-in-ovarian-clear-cell-carcinoma
#20
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
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