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Patients derived xenograft mouse model cancer (PDX)

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...
October 24, 2016: Nature Medicine
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
Dennis Wang, Nhu-An Pham, Jiefei Tong, Shingo Sakashita, Ghassan Allo, Lucia Kim, Naoki Yanagawa, Vibha Raghavan, Yuhong Wei, Christine To, Quang M Trinh, Maud H W Starmans, Michelle A Chan-Seng-Yue, Dianne Chadwick, Lei Li, Chang-Qi Zhu, Ni Liu, Ming Li, Sharon Lee, Vladimir Ignatchenko, Dan Strumpf, Paul Taylor, Nadeem Moghal, Geoffrey Liu, Paul C Boutros, Thomas Kislinger, Melania Pintilie, Igor Jurisica, Frances A Shepherd, John D McPherson, Lakshmi Muthuswamy, Michael F Moran, Ming-Sound Tsao
Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficient (NOD SCID) gamma mice...
October 17, 2016: International Journal of Cancer. Journal International du Cancer
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...
2016: Journal of Ovarian Research
Valentina E Schneeberger, Viola Allaj, Eric E Gardner, J T Poirier, Charles M Rudin
Patient-derived xenograft (PDX) mouse models are increasingly used for preclinical therapeutic testing of human cancer. A limitation in molecular and genetic characterization of PDX tumors is the presence of integral murine stroma. This is particularly problematic for genomic sequencing of PDX models. Rapid and dependable approaches for quantitating stromal content and purifying the malignant human component of these tumors are needed. We used a recently developed technique exploiting species-specific polymerase chain reaction (PCR) amplicon length (ssPAL) differences to define the fractional composition of murine and human DNA, which was proportional to the fractional composition of cells in a series of lung cancer PDX lines...
2016: PloS One
Bethany N Hannafon, Yvonne D Trigoso, Cameron L Calloway, Y Daniel Zhao, David H Lum, Alana L Welm, Zhizhuang J Zhao, Kenneth E Blick, William C Dooley, W Q Ding
BACKGROUND: microRNAs are promising candidate breast cancer biomarkers due to their cancer-specific expression profiles. However, efforts to develop circulating breast cancer biomarkers are challenged by the heterogeneity of microRNAs in the blood. To overcome this challenge, we aimed to develop a molecular profile of microRNAs specifically secreted from breast cancer cells. Our first step towards this direction relates to capturing and analyzing the contents of exosomes, which are small secretory vesicles that selectively encapsulate microRNAs indicative of their cell of origin...
2016: Breast Cancer Research: BCR
Kai M Brown, Aiqun Xue, Anubhav Mittal, Jaswinder S Samra, Ross Smith, Thomas J Hugh
AIMS: We sought to objectively assess the internal and external validity of patient-derived xenograft (PDX) models as a platform in pre-clinical research into colorectal cancer (CRC). Metastatic disease is the most common cause of death from CRC, and despite significant research, the results of current combination chemotherapy and targeted therapies have been underwhelming for most of this patient group. One of the key factors limiting the success of translational CRC research is the biologically inaccurate models in which new therapies are developed...
August 10, 2016: Oncotarget
Richard J Rebello, Eric Kusnadi, Donald P Cameron, Helen B Pearson, Analia Lesmana, Jennifer R Devlin, Denis Drygin, Ashlee K Clark, Laura Porter, John Pedersen, Shahneen Sandhu, Gail P Risbridger, Richard B Pearson, Ross D Hannan, Luc Furic
PURPOSE: The MYC oncogene is frequently over-expressed in prostate cancer (PC). Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. Additionally, PIM kinases activate MYC signaling and mRNA translation in PC and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat PC. EXPERIMENTAL DESIGN: The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription has been successfully exploited therapeutically, but only in models of hematological malignancy...
August 2, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Daniel P Nguyen, Peter L Xiong, He Liu, Samuel Pan, Wilhem Leconet, Vincent Navarro, Ming Guo, Jonathan Moy, Sae Kim, Marigdalia K Ramirez-Fort, Jaspreet S Batra, Neil H Bander
: Angiogenesis is critical for tumor growth and survival and involves interactions between cancer and endothelial cells. Prostate-specific membrane antigen (PSMA/FOLH1) is expressed in the neovasculature of several types of cancer. However, the study of neovascular PSMA expression has been impeded as human umbilical vein endothelial cell (HUVEC) cultures are PSMA-negative and both tumor xenografts and patient-derived xenograft (PDX) models are not known to express PSMA in their vasculature...
July 25, 2016: Molecular Cancer Research: MCR
Marta Paez-Ribes, Shan Man, Ping Xu, Robert S Kerbel
Several approaches are being evaluated to improve the historically limited value of studying transplanted primary tumors derived by injection of cells from established cell lines for predicting subsequent cancer therapy outcomes in patients and clinical trials. These approaches include use of genetically engineered mouse models (GEMMs) of spontaneous tumors, or patient tumor tissue derived xenografts (PDXs). Almost all such therapy studies utilizing such models involve treatment of established primary tumors...
2016: PloS One
Yu Wang, Xiwei Ding, Shaoqing Wang, Catherine D Moser, Hassan M Shaleh, Essa A Mohamed, Roongruedee Chaiteerakij, Loretta K Allotey, Gang Chen, Katsuyuki Miyabe, Melissa S McNulty, Albert Ndzengue, Emily G Barr Fritcher, Ryan A Knudson, Patricia T Greipp, Karl J Clark, Michael S Torbenson, Benjamin R Kipp, Jie Zhou, Michael T Barrett, Michael P Gustafson, Steven R Alberts, Mitesh J Borad, Lewis R Roberts
Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient...
September 28, 2016: Cancer Letters
Manman Deng, Zhiwu Jiang, Yin Li, Yong Zhou, Jie Li, Xiangmeng Wang, Yao Yao, Weiguang Wang, Peng Li, Bing Xu
Disulfiram (DS), a clinically used drug to control alcoholism, has displayed promising anti-cancer activity against a wide range of tumors. Here, we demonstrated that DS/copper (Cu) complex effectively eliminated adult B-ALL cells in vitro and in vivo in patient-derived xenograft (PDX) humanized mouse models, reflected by inhibition of cell proliferation, induction of apoptosis, suppression of colony formation, and reduction of PDX tumor growth, while sparing normal peripheral blood mononuclear cells. Mechanistically, these events were associated with disruption of mitochondrial membrane potential and down-regulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL...
May 17, 2016: Oncotarget
Rebecca S Lescarbeau, Liang Lei, Katrina K Bakken, Peter A Sims, Jann N Sarkaria, Peter Canoll, Forest M White
Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine-mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors...
June 2016: Molecular Cancer Therapeutics
Delphine Nicolle, Monique Fabre, Marina Simon-Coma, Aurore Gorse, Roland Kappler, Lara Nonell, Mar Mallo, Hazar Haidar, Olivier Déas, Charlotte Mussini, Catherine Guettier, Marie-José Redon, Laurence Brugières, Maria Rosa Ghigna, Elie Fadel, Louise Galmiche-Rolland, Christophe Chardot, Jean-Gabriel Judde, Carolina Armengol, Sophie Branchereau, Stefano Cairo
UNLABELLED: Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Liver cancer occurrence in infancy, 1.5 for million children per year, falls far below the threshold of interest for dedicated drug development programs, and this disease is so rare that it is very difficult to gather enough children into a phase II clinical trial. Here, we present the establishment of an unprecedented preclinical platform of 24 pediatric liver cancer patient-derived xenografts (PLC-PDXs) from 20 hepatoblastomas (HBs), 1 transitional liver cell tumor (TCLT), 1 hepatocellular carcinoma, and 2 malignant rhabdoid tumors...
October 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Takeshi Yoshikawa, Go Kobori, Takayuki Goto, Shusuke Akamatsu, Naoki Terada, Takashi Kobayashi, Yoshinori Tanaka, Giman Jung, Tomomi Kamba, Osamu Ogawa, Takahiro Inoue
BACKGROUND: The high rate of failure of new agents in oncology clinical trials indicates a weak understanding of the complexity of human cancer. Recent understanding of the mechanisms underlying castration resistance in prostate cancer led to the development of new agents targeting the androgen receptor pathway; however, their effectiveness is limited. Hence, there is a need for experimental systems that are able to better reproduce the biological diversity of prostate cancer in preclinical settings...
August 2016: Prostate
Yong Zhang, Makoto Toneri, Huaiyu Ma, Zhijian Yang, Michael Bouvet, Yusuke Goto, Naohiko Seki, Robert M Hoffman
There are two major types of mouse xenograft models of cancer: subcutaneous implantation and orthotopic implantation. Subcutaneous transplant models are widely used with both cancer cell lines and human-tumor specimens. Recently, subcutaneous models of patient tumors, termed patient-derived xenographs (PDX) have become highly popular and have acquired such names as "Avatar" and "Xenopatients." However, such s.c. models rarely metastasize and are therefore not patient-like. In contrast, orthotopic models have the capability to metastasize...
November 2016: Journal of Cellular Biochemistry
Rebecca S Lescarbeau, Liang Lei, Katrina K Bakken, Peter A Sims, Jann N Sarkaria, Peter Canoll, Forest M White
Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors...
March 23, 2016: Molecular Cancer Therapeutics
James R Bradford, Mark Wappett, Garry Beran, Armelle Logie, Oona Delpuech, Henry Brown, Joanna Boros, Nicola J Camp, Robert McEwen, Anne Marie Mazzola, Celina D'Cruz, Simon T Barry
The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type...
April 12, 2016: Oncotarget
Yoon Young Choi, Jae Eun Lee, Hyunki Kim, Moon Hee Sim, Ka-Kyung Kim, Gunho Lee, Hyoung-Il Kim, Ji Yeong An, Woo Jin Hyung, Choong-Bai Kim, Sung Hoon Noh, Sangwoo Kim, Jae-Ho Cheong
The patient-derived xenograft (PDX) model is emerging as a promising translational platform to duplicate the characteristics of tumours. However, few studies have reported detailed histological and genomic analyses for model fidelity and for factors affecting successful model establishment of gastric cancer. Here, we generated PDX tumours surgically-derived from 62 gastric cancer patients. Fifteen PDX models were successfully established (24.2%, 15/62) and passaged to maintain tumours in immune-compromised mice...
2016: Scientific Reports
Petra Martin, Erin Stewart, Nhu-An Pham, Celine Mascaux, Devang Panchal, Ming Li, Lucia Kim, Shingo Sakashita, Dennis Wang, Jenna Sykes, Thomas Friess, Frances A Shepherd, Geoffrey Liu, Ming-Sound Tsao
BACKGROUND: The epidermal growth factor receptor (EGFR) kinase domain T790M (amino acid substitution at position 790 in EGFR from threonine [T] to methionine [M]) mutation in non-small-cell lung cancer (NSCLC) results in resistance to EGFR tyrosine kinase inhibitors (TKIs). We used a patient-derived tumor xenograft (PDX) model containing an EGFR exon 19 deletion/T790M mutation to assess response to the EGFR-directed antibody cetuximab. Changes in the EGFR signaling pathway and ligand expression after treatment were investigated...
January 22, 2016: Clinical Lung Cancer
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