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DNA methylation in patient derived xenograft

Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
Mariam M AlHilli, Marc A Becker, S John Weroha, Karen S Flatten, Rachel M Hurley, Maria I Harrell, Ann L Oberg, Matt J Maurer, Kieran M Hawthorne, Xiaonan Hou, Sean C Harrington, Sarah McKinstry, X Wei Meng, Keith M Wilcoxen, Kimberly R Kalli, Elizabeth M Swisher, Scott H Kaufmann, Paul Haluska
OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo...
September 7, 2016: Gynecologic Oncology
Hye-Young Min, Su-Chan Lee, Jong Kyu Woo, Hyun Jin Jung, Kwan Hee Park, Hae Min Jeong, Seung Yeob Hyun, Jaebeom Cho, Wooin Lee, Ji Eun Park, So Jung Kwon, Hyo-Jong Lee, Xiao Ni, Young Kee Shin, Faye M Johnson, Madeleine Duvic, Ho-Young Lee
PURPOSE: Histone deacetylase inhibitors (HDIs) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study. EXPERIMENTAL DESIGN: The methylation status of CCCTC binding factor (CTCF)-binding sites in the IGF2/H19 imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing...
August 31, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qian Xiao, Donger Zhou, Agnieszka A Rucki, Jamila Williams, Jiaojiao Zhou, Guanglan Mo, Adrian Murphy, Kenji Fujiwara, Jennifer Kleponis, Bulent Salman, Christopher L Wolfgang, Robert A Anders, Shu Zheng, Elizabeth M Jaffee, Lei Zheng
Stromal fibrosis is a prominent histologic characteristic of pancreatic ductal adenocarcinoma (PDAC), but how stromal fibroblasts are regulated in the tumor microenvironment (TME) to support tumor growth is largely unknown. Here we show that PDAC cells can induce DNA methylation in cancer-associated fibroblasts (CAF). Upon direct contact with PDAC cells, DNA methylation of SOCS1 and other genes is induced in mesenchymal stem cells or in CAF that lack SOCS1 methylation at baseline. Silencing or decitabine treatment to block the DNA methylation enzyme DNMT1 inhibited methylation of SOCS1...
September 15, 2016: Cancer Research
Pascal O Zinn, Sanjay K Singh, Aikaterini Kotrotsou, Faramak Zandi, Ginu Thomas, Masumeh Hatami, Markus M Luedi, Ahmed Elakkad, Islam Hassan, Joy Gumin, Erik P Sulman, Frederick F Lang, Rivka R Colen
INTRODUCTION: Imaging is the modality of choice for noninvasive characterization of biological tissue and organ systems; imaging serves as early diagnostic tool for most disease processes and is rapidly evolving, thus transforming the way we diagnose and follow patients over time. A vast number of cancer imaging characteristics have been correlated to underlying genomics; however, none have established causality. Therefore, our objectives were to test if there is a causal relationship between imaging and genomic information; and to develop a clinically relevant radiomic pipeline for glioblastoma molecular characterization...
August 2016: Neurosurgery
Petra Ter Brugge, Petra Kristel, Eline van der Burg, Ute Boon, Michiel de Maaker, Esther Lips, Lennart Mulder, Julian de Ruiter, Catia Moutinho, Heidrun Gevensleben, Elisabetta Marangoni, Ian Majewski, Katarzyna Jóźwiak, Wigard Kloosterman, Markus van Roosmalen, Karen Duran, Frans Hogervorst, Nick Turner, Manel Esteller, Edwin Cuppen, Jelle Wesseling, Jos Jonkers
BACKGROUND: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. METHODS: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined...
November 2016: Journal of the National Cancer Institute
Brittany Kleb, Marcos R H Estécio, Jiexin Zhang, Vassiliki Tzelepi, Woonbok Chung, Jaroslav Jelinek, Nora M Navone, Salahaldin Tahir, Victor E Marquez, Jean-Pierre Issa, Sankar Maity, Ana Aparicio
Small cell prostate carcinoma (SCPC) morphology is rare at initial diagnosis but often emerges during prostate cancer progression and portends a dismal prognosis. It does not express androgen receptor (AR) or respond to hormonal therapies. Clinically applicable markers for its early detection and treatment with effective chemotherapy are needed. Our studies in patient tumor-derived xenografts (PDX) revealed that AR-negative SCPC (AR(-)SCPC) expresses neural development genes instead of the prostate luminal epithelial genes characteristic of AR-positive castration-resistant adenocarcinomas (AR(+)ADENO)...
March 3, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Claudia Maletzki, Maja Huehns, Patrick Knapp, Nancy Waukosin, Ernst Klar, Friedrich Prall, Michael Linnebacher
Patient-individual tumor models constitute a powerful platform for basic and translational analyses both in vitro and in vivo. However, due to the labor-intensive and highly time-consuming process, only few well-characterized patient-derived cell lines and/or corresponding xenografts exist. In this study, we describe successful generation and functional analysis of novel tumor models from patients with sporadic primary colorectal carcinomas (CRC) showing CpG island methylator phenotype (CIMP). Initial DNA fingerprint analysis confirmed identity with the patient in all four cases...
2015: PloS One
Shiv K Gupta, Sani H Kizilbash, Brett L Carlson, Ann C Mladek, Felix Boakye-Agyeman, Katrina K Bakken, Jenny L Pokorny, Mark A Schroeder, Paul A Decker, Ling Cen, Jeanette E Eckel-Passow, Gobinda Sarkar, Karla V Ballman, Joel M Reid, Robert B Jenkins, Roeland G Verhaak, Erik P Sulman, Gaspar J Kitange, Jann N Sarkaria
BACKGROUND: Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. METHODS: The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided...
May 2016: Journal of the National Cancer Institute
Michelle L Stewart, Pablo Tamayo, Andrew J Wilson, Stephanie Wang, Yun Min Chang, Jong W Kim, Dineo Khabele, Alykhan F Shamji, Stuart L Schreiber
Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells...
July 15, 2015: Cancer Research
J T Poirier, E E Gardner, N Connis, A L Moreira, E de Stanchina, C L Hann, C M Rudin
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations...
November 26, 2015: Oncogene
Rodrigo Goncalves, Wayne A Warner, Jingqin Luo, Matthew J Ellis
Massively parallel DNA and RNA sequencing approaches have generated data on thousands of breast cancer genomes. In this review, we consider progress largely from the perspective of new concepts and hypotheses raised so far. These include challenges to the multistep model of breast carcinogenesis and the discovery of new defects in DNA repair through sequence analysis. Issues for functional genomics include the development of strategies to differentiate between mutations that are likely to drive carcinogenesis and bystander background mutations, as well as the importance of mechanistic studies that examine the role of mutations in genes with roles in splicing, histone methylation, and long non-coding RNA function...
2014: Breast Cancer Research: BCR
Claudia Maletzki, Michael Gock, Martin Randow, Ernst Klar, Maja Huehns, Friedrich Prall, Michael Linnebacher
AIM: To generate novel tumor models for preclinical validation of biomarkers that allow drug response prediction and individual therapeutic decisions. METHODS: Cell line establishment was conducted by both direct in vitro culturing and in vivo xenografting followed by in vitro culturing procedure. A comprehensive characterization was subsequently performed. This included quality control, consisting of the confirmation of human and colorectal cancer (CRC) origin by DNA fingerprint and epithelial cell adhesion molecule (EpCAM) staining, as well as mycoplasma and human virus testing...
January 7, 2015: World Journal of Gastroenterology: WJG
Xiao-kun Wang, Jie-hua He, Jing-hong Xu, Sheng Ye, Fang Wang, Hui Zhang, Zhen-cong Huang, Kenneth Kin Wah To, Li-wu Fu
Cancer stem cells (CSC) have garnered significant attention as a therapeutic focus, based on evidence that they may represent an etiologic root of treatment-resistant cells. Indeed, expression of the multidrug resistance protein ATP-binding cassette subfamily G member 2 (ABCG2) confers chemoresistance to CSCs, where it serves as a potential biomarker and therapeutic target. Here, we show that afatinib, a small-molecule inhibitor of the tyrosine kinases EGFR, HER2, and HER4, preferentially eliminated side population cells with CSC character, in both cell lines and patient-derived leukemia cells, by decreasing ABCG2 expression...
August 15, 2014: Cancer Research
Nicholas C Wong, Vivek A Bhadri, Jovana Maksimovic, Mandy Parkinson-Bates, Jane Ng, Jeff M Craig, Richard Saffery, Richard B Lock
BACKGROUND: Patient-derived tumour xenografts are an attractive model for preclinical testing of anti-cancer drugs. Insights into tumour biology and biomarkers predictive of responses to chemotherapeutic drugs can also be gained from investigating xenograft models. As a first step towards examining the equivalence of epigenetic profiles between xenografts and primary tumours in paediatric leukaemia, we performed genome-scale DNA methylation and gene expression profiling on a panel of 10 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) tumours that were stratified by prednisolone response...
2014: BMC Genomics
Mehmet Baysan, Kevin Woolard, Serdar Bozdag, Gregory Riddick, Svetlana Kotliarova, Margaret C Cam, Galina I Belova, Susie Ahn, Wei Zhang, Hua Song, Jennifer Walling, Holly Stevenson, Paul Meltzer, Howard A Fine
In vitro and in vivo models are widely used in cancer research. Characterizing the similarities and differences between a patient's tumor and corresponding in vitro and in vivo models is important for understanding the potential clinical relevance of experimental data generated with these models. Towards this aim, we analyzed the genomic aberrations, DNA methylation and transcriptome profiles of five parental tumors and their matched in vitro isolated glioma stem cell (GSC) lines and xenografts generated from these same GSCs using high-resolution platforms...
2014: PloS One
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
Bing Z Carter, Po Yee Mak, Duncan H Mak, Yuexi Shi, Yihua Qiu, James M Bogenberger, Hong Mu, Raoul Tibes, Hui Yao, Kevin R Coombes, Rodrigo O Jacamo, Teresa McQueen, Steven M Kornblau, Michael Andreeff
BACKGROUND: Acute myeloid leukemia (AML) therapy has limited long-term efficacy because patients frequently develop disease relapse because of the inability of standard chemotherapeutic agents to target AML stem/progenitor cells. Here, we identify deregulated apoptotic components in AML stem/progenitor cells and investigate the individual and combinatorial effects of the novel inhibitor of apoptosis (IAP) protein antagonist and second mitochondrial-derived activator of caspases (SMAC) mimetic birinapant and demethylating epigenetic modulators...
February 2014: Journal of the National Cancer Institute
Pei-Ming Yang, Yi-Ting Lin, Chia-Tung Shun, Shan-Hu Lin, Tzu-Tang Wei, Shu-Hui Chuang, Ming-Shiang Wu, Ching-Chow Chen
Aberrant DNA hypermethylation is frequently found in tumor cells and inhibition of DNA methylation is an effective anticancer strategy. In this study, the therapeutic effect of DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) on colorectal cancer (CRC) was investigated. Zeb exhibited anticancer activity in cell cultures, tumor xenografts and mouse colitis-associated CRC model. It stabilizes p53 through ribosomal protein S7 (RPS7)/MDM2 pathways and DNA damage. Zeb-induced cell death was dependent on p53...
2013: Scientific Reports
Nicholas J Clemons, Hongdo Do, Christina Fennell, Siddhartha Deb, Andrew Fellowes, Alexander Dobrovic, Wayne A Phillips
BACKGROUND: Esophageal adenocarcinoma (EAC) has a very high case fatality rate and is one of the fastest rising cancers worldwide. At the same time, research into EAC has been hampered by a relative lack of pre-clinical models, including representative cell lines. AIM: The purpose of this study was to establish and characterize a new EAC cell line. METHODS: Tumor cells were isolated from EAC tissue by enzymatic digestion. Origin of the cell line was confirmed by microsatellite based genotyping...
January 2014: Digestive Diseases and Sciences
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