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JOURNAL ARTICLE
Yinu Wang, Xiaolei Situ, Horacio Cardenas, Ellie Siu, Razzaq A Alhunayan, Russell Keathley, Edward Tanner, Jianjun Wei, Yuying Tan, Chinmayee Vallabh Prabhu Dessai, Ji-Xin Cheng, Daniela Matei
PURPOSE: DNA methylation causes silencing of tumor suppressor and differentiation-associated genes, being linked to chemoresistance. Previous studies demonstrated that hypomethylating agents (HMA) re-sensitize ovarian cancer (OC) to chemotherapy. NTX-301 is a highly potent and orally bioavailable HMA, in early clinical development. EXPERIMENTAL DESIGN: The anti-tumor effects of NTX-301 were studied in OC models by using cell viability, stemness and ferroptosis assays, RNA sequencing, lipidomic analyses and stimulated Raman spectroscopy...
January 17, 2024: Clinical Cancer Research
#2
JOURNAL ARTICLE
Anna Rogojina, Laura J Klesse, Erin Butler, Jiwoong Kim, He Zhang, Xue Xiao, Lei Guo, Qinbo Zhou, Taylor Hartshorne, Dawn Garcia, Korri Weldon, Trevor Holland, Abhik Bandyopadhyay, Luz Perez Prado, Shidan Wang, Donghan M Yang, Anne-Marie Langevan, Yi Zou, Allison C Grimes, Chatchawin Assanasen, Vinod Gidvani-Diaz, Siyuan Zheng, Zhao Lai, Yidong Chen, Yang Xie, Gail E Tomlinson, Stephen X Skapek, Raushan T Kurmasheva, Peter J Houghton, Lin Xu
Patient-derived xenografts (PDX) remain valuable models for understanding the biology and for developing novel therapeutics. To expand current PDX models of childhood leukemia, we have developed new PDX models from Hispanic patients, a subgroup with a poorer overall outcome. Of 117 primary leukemia samples obtained, successful engraftment and serial passage in mice were achieved in 82 samples (70%). Hispanic patient samples engrafted at a rate (51/73, 70%) that was similar to non-Hispanic patient samples (31/45, 70%)...
November 17, 2023: IScience
#3
JOURNAL ARTICLE
Antoine Pinton, Lucien Courtois, Charlotte Doublet, Aurélie Cabannes-Hamy, Guillaume Andrieu, Charlotte Smith, Estelle Balducci, Agata Cieslak, Aurore Touzart, Mathieu Simonin, Veronique Lheritier, Francoise Huguet, Marie Balsat, Herve Dombret, Philippe Rousselot, Salvatore Spicuglia, Elizabeth Macintyre, Nicolas Boissel, Vahid Asnafi
PURPOSE: To assess the impact of PHF6 alterations on clinical outcome and therapeutical actionability in T cells acute lymphoblastic leukemia (T-ALL). EXPERIMENTAL DESIGN: We described PHF6 alterations in an adult cohort of T-ALL from the French trial GRAALL 2003/2005 and retrospectively analyzed clinical outcomes between PHF6-altered (PHF6ALT) and wild-type patients. We also used EPIC and ChIP-seq data of patient samples to analyze the epigenetic landscape of PHF6ALT T-ALLs...
October 27, 2023: Clinical Cancer Research
#4
JOURNAL ARTICLE
Oscar D Murillo, Varduhi Petrosyan, Emily L LaPlante, Lacey E Dobrolecki, Michael T Lewis, Aleksandar Milosavljevic
Proper characterization of cancer cell states within the tumor microenvironment is a key to accurately identifying matching experimental models and the development of precision therapies. To reconstruct this information from bulk RNA-seq profiles, we developed the XDec Simplex Mapping (XDec-SM) reference-optional deconvolution method that maps tumors and the states of constituent cells onto a biologically interpretable low-dimensional space. The method identifies gene sets informative for deconvolution from relevant single-cell profiling data when such profiles are available...
August 14, 2023: PLoS Computational Biology
#5
JOURNAL ARTICLE
Alex Clavería-Cabello, Jose Maria Herranz, Maria Ujue Latasa, Maria Arechederra, Iker Uriarte, Antonio Pineda-Lucena, Felipe Prosper, Pedro Berraondo, Cristina Alonso, Bruno Sangro, Jose Juan García Marin, Maria Luz Martinez-Chantar, Sergio Ciordia, Fernando José Corrales, Paola Francalanci, Rita Alaggio, Jessica Zucman-Rossi, Emilie Indersie, Stefano Cairo, Montserrat Domingo-Sàbat, Laura Zanatto, Pau Sancho-Bru, Carolina Armengol, Carmen Berasain, Maite García Fernandez-Barrena, Matias Antonio Avila
BACKGROUND & AIMS: Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis is needed to improve treatment. HB have a very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed to identify epigenetic regulators consistently dysregulated in HB and to evaluate the therapeutic efficacy of their targeting in clinically relevant models...
June 9, 2023: Journal of Hepatology
#6
JOURNAL ARTICLE
Lien Provez, Tom Putteman, Mattias Landfors, Juliette Roels, Lindy Reunes, Sara T'Sas, Wouter Van Loocke, Béatrice Lintermans, Stien De Coninck, Morgan Thenoz, Wouter Sleeckx, Natalia Maćkowska-Maślak, Tom Taghon, Marc R Mansour, Nadine Farah, Koen Norga, Peter Vandenberghe, Rishi S Kotecha, Steven Goossens, Sofie Degerman, Renate De Smedt, Pieter Van Vlierberghe
T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10-20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing. Here, we targeted the recently described DNA hypermethylated profile in T-LBL with the DNA hypomethylating agent decitabine...
January 20, 2023: Cancers
#7
JOURNAL ARTICLE
Verawan Boonsanay, Mohammed H Mosa, Mario Looso, Dieter Weichenhan, Fatih Ceteci, Lorenz Pudelko, Andre Lechel, Christian S Michel, Carsten Künne, Henner F Farin, Christoph Plass, Florian R Greten
BACKGROUND & AIMS: Epigenetic processes regulating gene expression contribute markedly to epithelial cell plasticity in colorectal carcinogenesis. The lysine methyltransferase SUV420H2 comprises an important regulator of epithelial plasticity and is primarily responsible for trimethylation of H4K20 (H4K20me3). Loss of H4K20me3 has been suggested as a hallmark of human cancer due to its interaction with DNMT1. However, the role of Suv4-20h2 in colorectal cancer is unknown. METHODS: We examined the alterations in histone modifications in patient-derived colorectal cancer organoids...
February 2023: Gastroenterology
#8
JOURNAL ARTICLE
Sibo Zhao, Jia Li, Huiyuan Zhang, Lin Qi, Yuchen Du, Mari Kogiso, Frank K Braun, Sophie Xiao, Yulun Huang, Jianfang Li, Wan-Yee Teo, Holly Lindsay, Patricia Baxter, Jack M F Su, Adekunle Adesina, Miklós Laczik, Paola Genevini, Anne-Clemence Veillard, Sol Schvartzman, Geoffrey Berguet, Shi-Rong Ding, Liping Du, Clifford Stephan, Jianhua Yang, Peter J A Davies, Xinyan Lu, Murali Chintagumpala, Donald William Parsons, Laszlo Perlaky, Yun-Fei Xia, Tsz-Kwong Man, Yun Huang, Deqiang Sun, Xiao-Nan Li
Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs)...
November 5, 2022: Nature Communications
#9
JOURNAL ARTICLE
Cheng-Long Hu, Bing-Yi Chen, Zijuan Li, Tianbiao Yang, Chun-Hui Xu, Ruirui Yang, Peng-Cheng Yu, Jingyao Zhao, Ting Liu, Na Liu, Bin Shan, Qunling Zhang, Junhong Song, Ming-Yue Fei, Li-Juan Zong, Jia-Ying Zhang, Ji-Chuan Wu, Shu-Bei Chen, Yong Wang, Binhe Chang, Dan Hou, Ping Liu, Yilun Jiang, Xiya Li, Xinchi Chen, Chu-Han Deng, Yi-Yi Ren, Roujia Wang, Jiacheng Jin, Kai Xue, Ying Zhang, Meirong Du, Jun Shi, Ling-Yun Wu, Chun-Kang Chang, Shuhong Shen, Zhu Chen, Sai-Juan Chen, Xiaolong Liu, Xiao-Jian Sun, Mingyue Zheng, Lan Wang
Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis...
December 2022: Cell Research
#10
JOURNAL ARTICLE
Julie A Shields, Samuel R Meier, Madhavi Bandi, Erin E Mulkearns-Hubert, Nicole Hajdari, Maria Dam Ferdinez, Justin L Engel, Daniel J Silver, Binzhang Shen, Wenhai Zhang, Christopher G Hubert, Kelly Mitchell, Sajina Shakya, Shan-Chuan Zhao, Alborz Bejnood, Minjie Zhang, Robert Tjin Tham Sjin, Erik Wilker, Justin D Lathia, Jannik N Andersen, Yingnan Chen, Fang Li, Barbara Weber, Alan Huang, Natasha Emmanuel
UNLABELLED: Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic-lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM...
November 2, 2022: Cancer Research
#11
JOURNAL ARTICLE
Tzu-Chun Kan, Mei-Hsiang Lin, Chun-Chia Cheng, Jeng-Wei Lu, Ming-Thau Sheu, Yuan-Soon Ho, Sri Rahayu, Jungshan Chang
Cisplatin is one of the most common therapeutics used in treatments of several types of cancers. To enhance cisplatin lipophilicity and reduce resistance and side effects, a polyfluorinated bipyridine-modified cisplatin analogue, dichloro[4,4'-bis(2,2,3,3-tetrafluoropropoxy)methyl)-2,2'-bipryridine] platinum (TFBPC), was synthesized and therapeutic assessments were performed. TFBPC displayed superior effects in inhibiting the proliferation of several cisplatin-resistant human cancer cell lines, including MDA-MB-231 breast cancers, COLO205 colon cancers and SK-OV-3 ovarian cancers...
April 11, 2022: Pharmaceutics
#12
JOURNAL ARTICLE
Lei Duan, Ricardo E Perez, Sarah Calhoun, Carl G Maki
The Jumonji C domain-containing family of histone lysine demethylases (Jumonji KDMs) have emerged as promising cancer therapy targets. These enzymes remove methyl groups from various histone lysines and, in turn, regulate processes including chromatin compaction, gene transcription, and DNA repair. Small molecule inhibitors of Jumonji KDMs have shown promise in preclinical studies against non-small cell lung cancer (NSCLC) and other cancers. However, how these inhibitors influence cancer therapy responses and/or DNA repair is incompletely understood...
December 31, 2022: Cancer Biology & Therapy
#13
JOURNAL ARTICLE
Marina da Costa Rosa, Alex Shimura Yamashita, Gregory J Riggins
BACKGROUND: Isocitrate Dehydrogenase 1/2 (IDH1/2) mutations are diagnostic for Astrocytoma or Oligodendroglioma, IDH-mutant. In these IDH-mutant gliomas, retinoic acid-related gene expression is commonly silenced by DNA hypermethylation. DNA demethylating agents can epigenetically reprogram IDH-mutant cells and reduce proliferation, likely by re-expression of silenced tumor suppressor pathways. We hypothesized that DNA demethylation might restore the retinoic acid pathway and slow tumor growth...
May 4, 2022: Neuro-oncology
#14
JOURNAL ARTICLE
Manvi Sharma, Itika Arora, Min Chen, Huixin Wu, Michael R Crowley, Trygve O Tollefsbol, Yuanyuan Li
Consumption of dietary natural components such as genistein (GE) found in soy-rich sources is strongly associated with a lower risk of breast cancer. However, bioactive dietary component-based therapeutic strategies are largely understudied in breast cancer treatment. Our investigation sought to elucidate the potential mechanisms linking bioactive dietary GE to its breast cancer chemotherapeutic potential in a special subtype of aggressive breast cancer-triple-negative breast cancer (TNBC)-by utilizing two preclinical patient-derived xenograft (PDX) orthotopic mouse models: BCM-3204 and TM00091...
November 4, 2021: Nutrients
#15
JOURNAL ARTICLE
Jeffrey W Johannes, Amber Balazs, Derek Barratt, Michal Bista, Matthew D Chuba, Sabina Cosulich, Susan E Critchlow, Sébastien L Degorce, Paolo Di Fruscia, Scott D Edmondson, Kevin Embrey, Stephen Fawell, Avipsa Ghosh, Sonja J Gill, Anders Gunnarsson, Sudhir M Hande, Tom D Heightman, Paul Hemsley, Giuditta Illuzzi, Jordan Lane, Carrie Larner, Elisabetta Leo, Lina Liu, Andrew Madin, Scott Martin, Lisa McWilliams, Mark J O'Connor, Jonathan P Orme, Fiona Pachl, Martin J Packer, Xiaohui Pei, Andrew Pike, Marianne Schimpl, Hongyao She, Anna D Staniszewska, Verity Talbot, Elizabeth Underwood, Jeffrey G Varnes, Lin Xue, Tieguang Yao, Ke Zhang, Andrew X Zhang, Xiaolan Zheng
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background...
September 27, 2021: Journal of Medicinal Chemistry
#16
JOURNAL ARTICLE
Kana Oiwa, Naoko Hosono, Rie Nishi, Luigi Scotto, Owen A O'Connor, Takahiro Yamauchi
BACKGROUND: Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic resistance or develop acquired resistance. Here, we evaluated the mechanisms underlying acquired resistance to PDX and explored potential therapeutic strategies to overcome PDX resistance. METHODS: To investigate PDX resistance, we established two PDX-resistant T-lymphoblastic leukemia cell lines (CEM and MOLT4) through continuous exposure to increasing doses of PDX...
July 31, 2021: BMC Cancer
#17
JOURNAL ARTICLE
Ksenija Nesic, Olga Kondrashova, Rachel M Hurley, Cordelia D McGehee, Cassandra J Vandenberg, Gwo-Yaw Ho, Elizabeth Lieschke, Genevieve Dall, Nirashaa Bound, Kristy Shield-Artin, Marc Radke, Ashan Musafer, Zi Qing Chai, Mohammad Reza Eftekhariyan Ghamsari, Maria I Harrell, Damien Kee, Inger Olesen, Orla McNally, Nadia Traficante, Australian Ovarian Cancer Study, Anna DeFazio, David D L Bowtell, Elizabeth M Swisher, S John Weroha, Katia Nones, Nicola Waddell, Scott H Kaufmann, Alexander Dobrovic, Matthew J Wakefield, Clare L Scott
In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (me RAD51C ) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the RAD51C promoter show responses to PARPi...
September 15, 2021: Cancer Research
#18
JOURNAL ARTICLE
Tao Gui, Ming Liu, Bing Yao, Haiqin Jiang, Dongjun Yang, Qixiang Li, Xiangwei Zeng, Ying Wang, Jian Cao, Yexuan Deng, Xinyu Li, Peipei Xu, Liqin Zhou, Dake Li, Zhihui Wang, Ke Zen, David C S Huang, Bing Chen, Guiping Wan, Quan Zhao
Endometrial cancer (EC) is the most common gynecological malignancy worldwide. However, the molecular mechanisms underlying EC progression are still largely unknown, and chemotherapeutic options for EC patients are currently very limited. In this study, we found that histone methyltransferase EZH2 and DNA methyltransferase DNMT3B were upregulated in EC samples from patients, and promoted EC cell proliferation as evidenced by assays of cell viability, cell cycle, colony formation. Mechanistically, we found that EZH2 promoted EC cell proliferation by epigenetically repressing TCF3, a direct transcriptional activator of CCKN1A (p21WAF1/Cip1 ), in vitro and in vivo...
June 26, 2021: Cell Death and Differentiation
#19
JOURNAL ARTICLE
Olga Bogatyrova, Johanna S M Mattsson, Edith M Ross, Michael P Sanderson, Max Backman, Johan Botling, Hans Brunnström, Pinja Kurppa, Linnéa La Fleur, Carina Strell, Claudia Wilm, Astrid Zimmermann, Christina Esdar, Patrick Micke
Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response. In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189)...
May 10, 2021: European Journal of Cancer
#20
REVIEW
Jiangman Liu, Guangping Lang, Jingshan Shi
Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia which is caused by insufficient insulin secretion or insulin resistance. Interaction of genetic, epigenetic and environmental factors plays a significant role in the development of T2DM. Several environmental factors including diet and lifestyle, as well as age have been associated with an increased risk for T2DM. It has been demonstrated that these environmental factors may affect global epigenetic status, and alter the expression of susceptible genes, thereby contributing to the pathogenesis of T2DM...
2021: Diabetes, Metabolic Syndrome and Obesity
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