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Patient derived xenograft and methylation

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https://www.readbyqxmd.com/read/28804556/anti-tumor-efficacy-evaluation-of-a-novel-monoclonal-antibody-targeting-neutral-amino-acid-transporter-asct2-using-patient-derived-xenograft-mouse-models-of-gastric-cancer
#1
Noriyuki Kasai, Aya Sasakawa, Kenta Hosomi, Tze Wei Poh, Bernadette Lynn Chua, Wei Peng Yong, Jimmy So, Shing Leng Chan, Richie Soong, Koji Kono, Toshihiko Ishii, Kazuya Yamano
ASC amino acid transporter 2 (ASCT2), also known as solute linked carrier family 1 member A5 (SLC1A5) is a Na+-dependent glutamine/neutral amino acid transporter. ASCT2 acts as a high-affinity transporter of L-glutamine (Gln) and has been reported to be up-regulated in a variety of cancerous tissues including stomach, liver, and kidney. In this study, we evaluated anti-tumor efficacy of a novel anti-ASCT2 humanized monoclonal antibody, KM8094, which has a neutralizing activity against glutamine uptake, as a therapeutic antibody against gastric cancer and explored clinical predictive biomarker candidates by utilizing patient-derived xenograft (PDX) mouse models...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28778066/inhibition-of-lsd1-epigenetically-attenuates-oral-cancer-growth-and-metastasis
#2
Saqer F Alsaqer, Mustafa M Tashkandi, Vinay K Kartha, Ya-Ting Yang, Yazeed Alkheriji, Andrew Salama, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti, Manish V Bais
Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase and a member of the amine oxidase (AO) family. LSD1 is a flavin-containing AO that specifically catalyzes the demethylation of mono- and di-methylated histone H3 lysine 4 through an FAD-dependent oxidative reaction. LSD1 is inappropriately upregulated in lung, liver, brain and esophageal cancers, where it promotes cancer initiation, progression, and metastasis. However, unlike other lysine-specific demethylases, the role and specific targets of LSD1 in oral squamous cell carcinoma (OSCC) pathogenesis remain unknown...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28729428/fluorine-18-labeled-carboplatin-derivative-for-pet-imaging-of-platinum-drug-distribution
#3
Narottam Lamichhane, Gajanan K Dewkar, Sundaresan Gobalakrishnan, Li Wang, Purnima Jose, Muhammad Otabashi, Jean-Luc Morelle, Nicholas Farrell, Jamal Zweit
Increasing evidence indicates that reduced intracellular drug accumulation is the parameter most consistently associated with platinum drug resistance, and emphasizes the need to directly measure intra-tumor drug concentration. In the era of precision medicine and with the advent of powerful imaging and proteomics technologies, there is an opportunity to better understand drug resistance, by exploiting these techniques to provide new knowledge on drug-target interactions. Here, we are contributing to this endeavor by reporting on the development of a fluorine-18 labeled carboplatin derivative ((18)F-FCP) that can be used to potentially image drug uptake and retention, including intra-tumoral distribution, by positron emission tomography (PET)...
July 20, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28729399/decitabine-priming-enhances-mucin-1-inhibition-mediated-disruption-of-redox-homeostasis-in-cutaneous-t-cell-lymphoma
#4
Salvia Jain, Abigail Washington, Rebecca Karp Leaf, Parul Bhargava, Rachael A Clark, Thomas S Kupper, Dina Stroopinsky, Athalia Pyzer, Leandra Cole, Myrna Nahas, Arie Apel, Jacalyn Rosenblatt, Jon Arnason, Donald Kufe, David Avigan
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the MUC1-C oncoprotein plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28625518/histone-chaperone-asf1a-predicts-poor-outcomes-for-patients-with-gastrointestinal-cancer-and-drives-cancer-progression-by-stimulating-transcription-of-%C3%AE-catenin-target-genes
#5
Xiuming Liang, Xiaotian Yuan, Jingya Yu, Yujiao Wu, Kailin Li, Chao Sun, Shuyan Li, Li Shen, Feng Kong, Jihui Jia, Magnus Björkholm, Dawei Xu
Epigenetic mechanisms play a key role in gastrointestinal cancer (GIC) development and progression, and most studies have been focused on aberrant DNA methylation and histone modifying enzymes. However, the histone H3-H4 chaperone ASF1A is an important factor regulating chromatin assembling and gene transcription, while it is currently unclear whether ASF1A is involved in cancer pathogenesis. The present study is thus designed to address this issue. Here we showed that ASF1A expression was widespread in GIC-derived cell lines and up-regulated in primary GIC...
July 2017: EBioMedicine
https://www.readbyqxmd.com/read/28581516/pancreatic-cancer-heterogeneity-and-response-to-mek-inhibition
#6
K Pedersen, F Bilal, C Bernadó Morales, M T Salcedo, T Macarulla, D Massó-Vallés, V Mohan, A Vivancos, M-J Carreras, X Serres, M Abu-Suboh, J Balsells, E Allende, I Sagi, L Soucek, J Tabernero, J Arribas
Our increasing knowledge of the mechanisms behind the progression of pancreatic cancer (PC) has not yet translated into effective treatments. Many promising drugs have failed in the clinic, highlighting the need for better preclinical models to assess drug efficacy and characterize mechanisms of resistance. Using different experimental models, including patient-derived xenografts (PDXs), we gauged the efficacy of therapies aimed at two hallmark lesions of PCs: activation of signaling pathways by oncogenic KRAS and inactivation of tumor-suppressor genes...
June 5, 2017: Oncogene
https://www.readbyqxmd.com/read/28581514/aldh1a3-is-epigenetically-regulated-during-melanocyte-transformation-and-is-a-target-for-melanoma-treatment
#7
M Pérez-Alea, K McGrail, S Sánchez-Redondo, B Ferrer, G Fournet, J Cortés, E Muñoz, J Hernandez-Losa, S Tenbaum, G Martin, R Costello, I Ceylan, V Garcia-Patos, J A Recio
Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity...
June 5, 2017: Oncogene
https://www.readbyqxmd.com/read/28564604/cancer-associated-idh1-promotes-growth-and-resistance-to-targeted-therapies-in-the-absence-of-mutation
#8
Andrea E Calvert, Alexandra Chalastanis, Yongfei Wu, Lisa A Hurley, Fotini M Kouri, Yingtao Bi, Maureen Kachman, Jasmine L May, Elizabeth Bartom, Youjia Hua, Rama K Mishra, Gary E Schiltz, Oleksii Dubrovskyi, Andrew P Mazar, Marcus E Peter, Hongwu Zheng, C David James, Charles F Burant, Navdeep S Chandel, Ramana V Davuluri, Craig Horbinski, Alexander H Stegh
Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBMs. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs the survival of animal subjects bearing patient-derived xenografts (PDXs)...
May 30, 2017: Cell Reports
https://www.readbyqxmd.com/read/28536141/melk-and-ezh2-cooperate-to-regulate-medulloblastoma-cancer-stem-like-cell-proliferation-and-differentiation
#9
Hailong Liu, Qianwen Sun, Youliang Sun, Junping Zhang, Hongyu Yuan, Shuhuan Pang, Xueling Qi, Haoran Wang, Mingshan Zhang, Hongwei Zhang, Chunjiang Yu, Chunyu Gu
Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stem-like cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma...
May 23, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28417956/establishment-and-characterization-of-an-orthotopic-patient-derived-group-3-medulloblastoma-model-for-preclinical-drug-evaluation
#10
Emma Sandén, Cecilia Dyberg, Cecilia Krona, Gabriel Gallo-Oller, Thale Kristin Olsen, Julio Enríquez Pérez, Malin Wickström, Atosa Estekizadeh, Marcel Kool, Edward Visse, Tomas J Ekström, Peter Siesjö, John Inge Johnsen, Anna Darabi
Medulloblastomas comprise a heterogeneous group of tumours and can be subdivided into four molecular subgroups (WNT, SHH, Group 3 and Group 4) with distinct prognosis, biological behaviour and implications for targeted therapies. Few experimental models exist of the aggressive and poorly characterized Group 3 tumours. In order to establish a reproducible transplantable Group 3 medulloblastoma model for preclinical therapeutic studies, we acquired a patient-derived tumour sphere culture and inoculated low-passage spheres into the cerebellums of NOD-scid mice...
April 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28228601/loss-of-tumor-suppressor-kdm6a-amplifies-prc2-regulated-transcriptional-repression-in-bladder-cancer-and-can-be-targeted-through-inhibition-of-ezh2
#11
Lian Dee Ler, Sujoy Ghosh, Xiaoran Chai, Aye Aye Thike, Hong Lee Heng, Ee Yan Siew, Sucharita Dey, Liang Kai Koh, Jing Quan Lim, Weng Khong Lim, Swe Swe Myint, Jia Liang Loh, Pauline Ong, Xin Xiu Sam, Dachuan Huang, Tony Lim, Puay Hoon Tan, Sanjanaa Nagarajan, Christopher Wai Sam Cheng, Henry Ho, Lay Guat Ng, John Yuen, Po-Hung Lin, Cheng-Keng Chuang, Ying-Hsu Chang, Wen-Hui Weng, Steven G Rozen, Patrick Tan, Caretha L Creasy, See-Tong Pang, Michael T McCabe, Song Ling Poon, Bin Tean Teh
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type...
February 22, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28159862/temozolomide-in-the-era-of-precision-medicine
#12
REVIEW
Anish Thomas, Mamoru Tanaka, Jane Trepel, William C Reinhold, Vinodh N Rajapakse, Yves Pommier
In the January 1, 2017, issue of Cancer Research, Nagel and colleagues demonstrate the value of assays that determine the DNA repair capacity of cancers in predicting response to temozolomide. Using a fluorescence-based multiplex flow cytometric host cell reactivation assay that provides simultaneous readout of DNA repair capacity across multiple pathways, they show that the multivariate drug response models derived from cell line data were applicable to patient-derived xenograft models of glioblastoma. In this commentary, we first outline the mechanism of activity and current clinical application of temozolomide, which, until now, has been largely limited to glioblastoma...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28093071/spag6-and-l1td1-are-transcriptionally-regulated-by-dna-methylation-in-non-small-cell-lung-cancers
#13
Corinna Altenberger, Gerwin Heller, Barbara Ziegler, Erwin Tomasich, Maximilian Marhold, Thais Topakian, Leonhard Müllauer, Petra Heffeter, György Lang, Adelheid End-Pfützenreuter, Balazs Döme, Britt-Madeleine Arns, Walter Klepetko, Christoph C Zielinski, Sabine Zöchbauer-Müller
BACKGROUND: DNA methylation regulates together with other epigenetic mechanisms the transcriptional activity of genes and is involved in the pathogenesis of malignant diseases including lung cancer. In non-small cell lung cancer (NSCLC) various tumor suppressor genes are already known to be tumor-specifically methylated. However, from the vast majority of a large number of genes which were identified to be tumor-specifically methylated, tumor-specific methylation was unknown so far. Thus, the major aim of this study was to investigate in detail the mechanism(s) responsible for transcriptional regulation of the genes SPAG6 and L1TD1 in NSCLCs...
January 5, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28040796/role-of-rpl39-in-metaplastic-breast-cancer
#14
Bhuvanesh Dave, Daniel D Gonzalez, Zhi-Bin Liu, Xiaoxian Li, Helen Wong, Sergio Granados, Nadeer E Ezzedine, Douglas H Sieglaff, Joe E Ensor, Kathy D Miller, Milan Radovich, Agda KarinaEtrovic, Steven S Gross, Olivier Elemento, Gordon B Mills, Michael Z Gilcrease, Jenny C Chang
Background: Metaplastic breast cancer is one of the most therapeutically challenging forms of breast cancer because of its highly heterogeneous and chemoresistant nature. We have previously demonstrated that ribosomal protein L39 (RPL39) and its gain-of-function mutation A14V have oncogenic activity in triple-negative breast cancer and this activity may be mediated through inducible nitric oxide synthase (iNOS). The function of RPL39 and A14V in other breast cancer subtypes is currently unknown...
June 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27872496/inactivation-of-klf4-promotes-t-cell-acute-lymphoblastic-leukemia-and-activates-the-map2k7-pathway
#15
Y Shen, C S Park, K Suppipat, T-A Mistretta, M Puppi, T M Horton, K Rabin, N S Gray, J P P Meijerink, H D Lacorazza
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a high incidence of relapse in pediatric ALL. Although most T-ALL patients exhibit activating mutations in NOTCH1, the cooperating genetic events required to accelerate the onset of leukemia and worsen disease progression are largely unknown. Here, we show that the gene encoding the transcription factor KLF4 is inactivated by DNA methylation in children with T-ALL. In mice, loss of KLF4 accelerated the development of NOTCH1-induced T-ALL by enhancing the G1-to-S transition in leukemic cells and promoting the expansion of leukemia-initiating cells...
June 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27837553/biobanking-an-important-resource-for-precision-medicine-in-glioblastoma
#16
Si Yan Melanie Tan, Edwin Sandanaraj, Carol Tang, Beng Ti Christopher Ang
The Cancer Genome Atlas effort has generated significant interest in a new paradigm shift in tumor tissue analysis, patient diagnosis and subsequent treatment decision. Findings have highlighted the limitation of sole reliance on histology, which can be confounded by inter-observer variability. Such studies demonstrate that histologically similar grade IV brain tumors can be divided into four molecular subtypes based on gene expression, with each subtype demonstrating unique genomic aberrations and clinical outcome...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27765857/assessment-of-tryptophan-uptake-and-kinetics-using-1-2-18f-fluoroethyl-l-tryptophan-and-%C3%AE-11c-methyl-l-tryptophan-pet-imaging-in-mice-implanted-with-patient-derived-brain-tumor-xenografts
#17
Sharon K Michelhaugh, Otto Muzik, Anthony R Guastella, Neil V Klinger, Lisa A Polin, Hancheng Cai, Yangchun Xin, Thomas J Mangner, Shaohui Zhang, Csaba Juhász, Sandeep Mittal
Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. α-(11)C-methyl-l-tryptophan ((11)C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of (11)C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-(18)F-fluoroethyl)-l-tryptophan ((18)F-FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway...
February 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/27765068/genome-wide-methylation-profiling-of-ovarian-cancer-patient-derived-xenografts-treated-with-the-demethylating-agent-decitabine-identifies-novel-epigenetically-regulated-genes-and-pathways
#18
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
https://www.readbyqxmd.com/read/27750381/molecular-heterogeneity-of-non-small-cell-lung-carcinoma-patient-derived-xenografts-closely-reflect-their-primary-tumors
#19
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...
February 1, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27742014/kdm4c-a-h3k9me3-histone-demethylase-is-involved-in-the-maintenance-of-human-escc-initiating-cells-by-epigenetically-enhancing-sox2-expression
#20
Xiang Yuan, Jinyu Kong, Zhikun Ma, Na Li, Ruinuo Jia, Yiwen Liu, Fuyou Zhou, Qimin Zhan, Gang Liu, Shegan Gao
Our studies investigating the existence of tumor-initiating cell (TIC) populations in human esophageal squamous cell carcinoma (ESCC) had identified a subpopulation of cells isolated from ESCC patient-derived tumor specimens marked by an ALDH(bri+) phenotype bear stem cell-like features. Importantly, KDM4C, a histone demethylase was enhanced in ALDH(bri+) subpopulation, suggesting that strategies interfering with KDM4C may be able to target these putative TICs. In the present study, by genetic and chemical means, we demonstrated that, KDM4C blockade selectively decreased the ESCC ALDH(bri+) TICs population in vitro and specifically targeted the TICs in ALDH(bri+)-derived xenograft, retarding engraftment...
October 2016: Neoplasia: An International Journal for Oncology Research
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