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Ovarian PDX mice model

Paulina Cybulska, Jocelyn M Stewart, Azin Sayad, Carl Virtanen, Patricia A Shaw, Blaise Clarke, Natalie Stickle, Marcus Q Bernardini, Benjamin G Neel
High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignant tumors. Overall survival remains low because of the nearly ubiquitous emergence of platinum resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for preclinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment...
May 2018: American Journal of Pathology
Elizabeth Magnotti, Wayne A Marasco
Epithelial ovarian cancer is a heterogeneous disease classified into five subtypes, each with a different molecular profile. Most cases of ovarian cancer are diagnosed after metastasis of the primary tumor and are resistant to traditional platinum-based chemotherapeutics. Mouse models of ovarian cancer have been utilized to discern ovarian cancer tumorigenesis and the tumor's response to therapeutics. Areas covered: The authors provide a review of mouse models currently employed to understand ovarian cancer...
March 2018: Expert Opinion on Drug Discovery
Chel Hun Choi, Ji-Yoon Ryu, Young-Jae Cho, Hye-Kyung Jeon, Jung-Joo Choi, Kris Ylaya, Yoo-Young Lee, Tae-Joong Kim, Joon-Yong Chung, Stephen M Hewitt, Byoung-Gie Kim, Duk-Soo Bae, Jeong-Won Lee
We assessed the anti-proliferative activity of itraconazole using an EOC cell line (SKOV3ip1) and endothelial cell lines (HUVEC & SVEC4-10). We also examined angiogenesis (VEGFR2, p-ERK, p-PLCr1/2), hedgehog (Gli1, Ptch1, SMO), and mTOR (pS6K1) signaling pathways to determine the mechanism of action of itraconazole. Furthermore, we evaluated the synergistic effects of itraconazole and paclitaxel using orthotopic mouse models with established EOC cells (SKOV3ip1 or HeyA8) as well as patient-derived xenografts (PDXs)...
July 26, 2017: Scientific Reports
Kristina A Butler, Xiaonan Hou, Marc A Becker, Valentina Zanfagnin, Sergio Enderica-Gonzalez, Daniel Visscher, Kimberly R Kalli, Piyawan Tienchaianada, Paul Haluska, S John Weroha
Interest in preclinical drug development for ovarian cancer has stimulated development of patient-derived xenograft (PDX) or tumorgraft models. However, the unintended formation of human lymphoma in severe combined immunodeficiency (SCID) mice from Epstein-Barr virus (EBV)-infected human lymphocytes can be problematic. In this study, we have characterized ovarian cancer PDXs which developed human lymphomas and explore methods to suppress lymphoproliferative growth. Fresh human ovarian tumors from 568 patients were transplanted intraperitoneally in SCID mice...
August 2017: Neoplasia: An International Journal for Oncology Research
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...
October 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Leslie A Garrett, Whitfield B Growdon, Bo R Rueda, Rosemary Foster
BACKGROUND: Pre-clinical studies have demonstrated that natural and synthetic histone deacetylase (HDAC) inhibitors can impede the in vitro and in vivo growth of cell lines from a variety of gynecologic and other malignancies. We investigated the anti-tumor activity of panobinostat (LBH589) both in vitro and in vivo as either a single agent or in combination with conventional cytotoxic chemotherapy using patient-derived xenograft (PDX) models of primary serous ovarian tumors. METHODS: The ovarian cancer cell lines OVCAR8, SKOV3 and their paclitaxel-resistant derivatives OVCAR8-TR and SKOV3-TR were treated with increasing doses of LBH589...
September 15, 2016: Journal of Ovarian Research
Brittney S Harrington, Yaowu He, Claire M Davies, Sarah J Wallace, Mark N Adams, Elizabeth A Beaven, Deborah K Roche, Catherine Kennedy, Naven P Chetty, Alexander J Crandon, Christopher Flatley, Niara B Oliveira, Catherine M Shannon, Anna deFazio, Anna V Tinker, C Blake Gilks, Brian Gabrielli, Donal J Brennan, Jermaine I Coward, Jane E Armes, Lewis C Perrin, John D Hooper
BACKGROUND: Development of targeted therapies for high-grade serous ovarian cancer (HGSC) remains challenging, as contributing molecular pathways are poorly defined or expressed heterogeneously. CUB-domain containing protein 1 (CDCP1) is a cell-surface protein elevated in lung, colorectal, pancreas, renal and clear cell ovarian cancer. METHODS: CUB-domain containing protein 1 was examined by immunohistochemistry in HGSC and fallopian tube. The impact of targeting CDCP1 on cell growth and migration in vitro, and intraperitoneal xenograft growth in mice was examined...
February 16, 2016: British Journal of Cancer
Amira A Zayed, Sumithra J Mandrekar, Paul Haluska
Innovation in oncology drug development has been hindered by lack of preclinical models that reliably predict clinical activity of novel therapies in cancer patients. Increasing desire for individualize treatment of patients with cancer has led to an increase in the use of patient-derived xenografts (PDX) engrafted into immune-compromised mice for preclinical modeling. Large numbers of tumor-specific PDX models have been established and proved to be powerful tools in pre-clinical testing. A subset of PDXs, referred to as Avatars, establish tumors in an orthotopic and treatment naïve fashion that may represent the most clinical relevant model of individual human cancers...
September 2015: Chinese Clinical Oncology
Pierre-Emmanuel Colombo, Stanislas du Manoir, Béatrice Orsett, Rui Bras-Gonçalves, Mario B Lambros, Alan MacKay, Tien-Tuan Nguyen, Florence Boissière, Didier Pourquier, Frédéric Bibeau, Jorge S Reis-Filho, Charles Theillet
Advanced Epithelial Ovarian Cancer (EOC) patients frequently relapse by 24 months and develop resistant disease. Research on EOC therapies relies on cancer cell lines established decades ago making Patient Derived Xenografts (PDX) attractive models, because they are faithful representations of the original tumor. We established 35 ovarian cancer PDXs resulting from the original graft of 77 EOC samples onto immuno-compromised mice. PDXs covered the diversity of EOC histotypes and graft take was correlated with early patient death...
September 29, 2015: Oncotarget
Alessandra Decio, Marta Cesca, Francesca Bizzaro, Luca Porcu, Rossana Bettolini, Paolo Ubezio, Giulia Taraboletti, Dorina Belotti, Raffaella Giavazzi
Cediranib is a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor that affects tumor angiogenesis and is under investigation in clinical studies on ovarian cancer. Using a panel of eleven patient-derived ovarian cancer xenografts (EOC-PDX) growing orthotopically in the peritoneal cavity of nude mice we investigated the effect of cediranib as monotherapy or in combination with chemotherapy on overall survival (primary endpoint, at euthanasia), and tumor dissemination and metastasis in the peritoneal cavity (secondary endpoint, interim analysis)...
October 2015: Clinical & Experimental Metastasis
Emiliano Cocco, Erik M Shapiro, Sara Gasparrini, Salvatore Lopez, Carlton L Schwab, Stefania Bellone, Ileana Bortolomai, Natalia J Sumi, Elena Bonazzoli, Roberta Nicoletti, Yang Deng, W Mark Saltzman, Caroline J Zeiss, Floriana Centritto, Jonathan D Black, Dan-Arin Silasi, Elena Ratner, Masoud Azodi, Thomas J Rutherford, Peter E Schwartz, Sergio Pecorelli, Alessandro D Santin
Identification of micrometastatic disease at the time of surgery remains extremely challenging in ovarian cancer patients. We used fluorescence microscopy, an in vivo imaging system and a fluorescence stereo microscope to evaluate fluorescence distribution in Claudin-3- and -4-overexpressing ovarian tumors, floating tumor clumps isolated from ascites and healthy organs. To do so, mice harboring chemotherapy-naïve and chemotherapy-resistant human ovarian cancer xenografts or patient-derived xenografts (PDXs) were treated with the carboxyl-terminal binding domain of the Clostridium perfringens enterotoxin (c-CPE) conjugated to FITC (FITC-c-CPE) or the near-infrared (NIR) fluorescent tag IRDye CW800 (CW800-c-CPE) either intraperitoneally (IP) or intravenously (IV)...
December 1, 2015: International Journal of Cancer. Journal International du Cancer
K Lodhia, M Becker, X Hou, K Kalli, M Harrell, K Wilcoxen, E Swisher, S Weroha, P Halsuka
Ovarian cancer is the most lethal gynecologic malignancy. Current standard of care post surgical cytoreduction is combination platinum/taxane chemotherapy, with initial response varying widely; subsets of carcinomas demonstrate resistance or sensitivity from the onset. The underlying cause of this response heterogeneity remains unknown. Patient-derived xenografts (PDX) serve as useful in vivo models to study molecular response markers and test the efficacy of targeted therapies. Our group has demonstrated a high engraftment rate (>70%) of ovarian cancer PDXs (Avatars) by injecting treatment naïve patient tumor directly into the peritoneal cavity of immunocompromised mice, in an effort to better mimic the anatomic context by which ovarian cancer naturally develops...
March 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Clare L Scott, Helen J Mackay, Paul Haluska
In the era of targeted therapies, patients with gynecologic malignancies have not yet been major beneficiaries of this new class of agents. This may reflect the fact that the main tumor types-ovarian, uterine, and cervical--are a highly heterogeneous group of cancers with variable response to standard chemotherapies and the lack of models in which to study the diversity of these cancers. Cancer-derived cell lines fail to adequately recapitulate molecular hallmarks of specific cancer subsets and complex microenvironments, which may be critical for sensitivity to targeted therapies...
2014: American Society of Clinical Oncology Educational Book
Monique D Topp, Lynne Hartley, Michele Cook, Valerie Heong, Emma Boehm, Lauren McShane, Jan Pyman, Orla McNally, Sumitra Ananda, Marisol Harrell, Dariush Etemadmoghadam, Laura Galletta, Kathryn Alsop, Gillian Mitchell, Stephen B Fox, Jeffrey B Kerr, Karla J Hutt, Scott H Kaufmann, Australian Ovarian Cancer Study, Elizabeth M Swisher, David D Bowtell, Matthew J Wakefield, Clare L Scott
INTRODUCTION: Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses. METHODS: We generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naïve, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rγ(null) recipient mice, completed molecular annotation and assessed platinum sensitivity...
May 2014: Molecular Oncology
Clare L Scott, Marc A Becker, Paul Haluska, Goli Samimi
Despite increasing evidence that precision therapy targeted to the molecular drivers of a cancer has the potential to improve clinical outcomes, high-grade epithelial ovarian cancer (OC) patients are currently treated without consideration of molecular phenotype, and predictive biomarkers that could better inform treatment remain unknown. Delivery of precision therapy requires improved integration of laboratory-based models and cutting-edge clinical research, with pre-clinical models predicting patient subsets that will benefit from a particular targeted therapeutic...
2013: Frontiers in Oncology
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