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Mocetinostat

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https://www.readbyqxmd.com/read/29238851/phase-i-ii-study-of-mocetinostat-in-combination-with-gemcitabine-for-patients-with-advanced-pancreatic-cancer-and-other-advanced-solid-tumors
#1
Emily Chan, E Gabriela Chiorean, Peter J O'Dwyer, Nashat Y Gabrail, Thierry Alcindor, Diane Potvin, Richard Chao, Herbert Hurwitz
PURPOSE: To evaluate the safety and efficacy of mocetinostat (a Class I/IV HDAC inhibitor) in combination with gemcitabine in patients with solid tumors, including pancreatic cancer. METHODS: In this open-label, non-randomized Phase I/II study (NCT00372437) sequential cohorts of patients with solid tumors received gemcitabine (1000 mg/m2, day 1 of three consecutive weeks, 4-week cycles) and oral mocetinostat [50-110 mg, three times per week (TIW)]. The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) was determined based on dose-limiting toxicities in Cycle 1 (Phase I study)...
December 13, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29186204/mocetinostat-combined-with-gemcitabine-for-the-treatment-of-leiomyosarcoma-preclinical-correlates
#2
Gonzalo Lopez, Danielle Braggio, Abeba Zewdu, Lucia Casadei, Kara Batte, Hemant Kumar Bid, David Koller, Peter Yu, Obiajulu Hans Iwenofu, Anne Strohecker, Edwin Choy, Dina Lev, Raphael Pollock
Leiomyosarcoma (LMS) is a malignant soft tissue sarcoma (STS) with a dismal prognosis following metastatic disease. Chemotherapeutic intervention has demonstrated to have modest clinical efficacy with no curative potential in LMS patients. Previously, we demonstrated pan-HDAC inhibition to have a superior effect in various complex karyotypic sarcomas. In this study, our goal is to evaluate the therapeutic efficacy of mocetinostat alone and in combination with gemcitabine in LMS. Human leiomyosarcoma (LMS) cell lines were used for in vitro and in vivo studies...
2017: PloS One
https://www.readbyqxmd.com/read/29124315/the-class-i-iv-hdac-inhibitor-mocetinostat-increases-tumor-antigen-presentation-decreases-immune-suppressive-cell-types-and-augments-checkpoint-inhibitor-therapy
#3
David Briere, Niranjan Sudhakar, David M Woods, Jill Hallin, Lars D Engstrom, Ruth Aranda, Harrah Chiang, Andressa L Sodré, Peter Olson, Jeffrey S Weber, James G Christensen
Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells...
November 9, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28970362/functional-impact-of-chromatin-remodeling-gene-mutations-and-predictive-signature-for-therapeutic-response-in-bladder-cancer
#4
Jason E Duex, Kalin E Swain, Garrett M Dancik, Richard D Paucek, Charles Owens, Mair E A Churchill, Dan Theodorescu
Urothelial carcinoma accounts for most the of bladder cancer cases. Using next-generation sequencing (NGS) technologies we found that a significant percentage (83%) of tumors had mutations in chromatin remodeling genes. Here, we examined the functional relevance of mutations in two chromatin remodeling genes, EP300 and its paralog, CREBBP, which are mutated in almost a third of patients. Interestingly, almost half of missense mutations cluster in the histone-acetyltransferase (HAT) domain of EP300/CREBBP. This domain catalyzes the transfer of an acetyl group to target molecules such as histones, thereby regulating chromatin dynamics...
October 2, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28870998/histone-deacetylases-as-new-therapeutic-targets-in-triple-negative-breast-cancer-progress-and-promises
#5
REVIEW
Nikolaos Garmpis, Christos Damaskos, Anna Garmpi, Emmanouil Kalampokas, Theodoros Kalampokas, Eleftherios Spartalis, Afrodite Daskalopoulou, Serena Valsami, Michael Kontos, Afroditi Nonni, Konstantinos Kontzoglou, Despina Perrea, Nikolaos Nikiteas, Dimitrios Dimitroulis
Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 gene. It comprises approximately 15-20% of breast cancers (BCs). Unfortunately, TNBC's treatment continues to be a clinical problem because of its relatively poor prognosis, its aggressiveness and the lack of targeted therapies, leaving chemotherapy as the mainstay of treatment. It is essential to find new therapies against TNBC, in order to surpass the resistance and the invasiveness of already existing therapies...
September 2017: Cancer Genomics & Proteomics
https://www.readbyqxmd.com/read/28839000/radiosensitisation-in-vivo-by-histone-deacetylase-inhibition-with-no-increase-in-early-normal-tissue-radiation-toxicity
#6
Blaz Groselj, Jia-Ling Ruan, Helen Scott, Jessica Gorrill, Judith Nicholson, Jacqueline Kelly, Selvakumar Anbalagan, James Thompson, Michael Rl Stratford, Sarah J Jevons, Ester M Hammond, Cheryl L Scudamore, Martin Kerr, Anne E Kiltie
As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitising agents minimally toxic to normal tissues, including bowel and bladder, for such patients. We developed methods to determine normal tissue toxicity severity in intestine and bladder in vivo, using novel radiotherapy techniques on a small animal radiation research platform (SARRP)...
August 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28560068/hdac2-overexpression-correlates-with-aggressive-clinicopathological-features-and-dna-damage-response-pathway-of-breast-cancer
#7
Wenqi Shan, Yuanyuan Jiang, Huimei Yu, Qianhui Huang, Lanxin Liu, Xuhui Guo, Lei Li, Qingsheng Mi, Kezhong Zhang, Zengquan Yang
There are 18 lysine deacetylases, also known as histone deacetylases (HDACs), that remove acetyl groups from histone and non-histone proteins, thereby playing critical roles in numerous biological processes. In many human cancers, HDACs are dysregulated through mutation, altered expression, or inappropriate recruitment to certain loci. However, knowledge of the genomic and transcriptomic alterations and the clinical significance of most HDACs in breast cancer remain incomplete. We used TCGA and METABRIC datasets to perform comprehensive, integrated genomic and transcriptomic analyses of 18 HDAC genes in approximately 3000 primary breast cancers and identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28440559/a-phase-2-study-of-mocetinostat-a-histone-deacetylase-inhibitor-in-relapsed-or-refractory-lymphoma
#8
MULTICENTER STUDY
Connie L Batlevi, Michael Crump, Charalambos Andreadis, David Rizzieri, Sarit E Assouline, Susan Fox, Richard H C van der Jagt, Amanda Copeland, Diane Potvin, Richard Chao, Anas Younes
Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70-110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31)...
August 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28276480/selective-targeting-of-hdac1-2-elicits-anticancer-effects-through-gli1-acetylation-in-preclinical-models-of-shh-medulloblastoma
#9
Sonia Coni, Anna Barbara Mancuso, Laura Di Magno, Giulia Sdruscia, Simona Manni, Silvia Maria Serrao, Dante Rotili, Eleonora Spiombi, Francesca Bufalieri, Marialaura Petroni, Monika Kusio-Kobialka, Enrico De Smaele, Elisabetta Ferretti, Carlo Capalbo, Antonello Mai, Pawel Niewiadomski, Isabella Screpanti, Lucia Di Marcotullio, Gianluca Canettieri
SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28077797/repression-of-fyn-related-kinase-in-breast-cancer-cells-is-associated-with-promoter-site-specific-cpg-methylation
#10
Edward T Bagu, Sayem Miah, Chenlu Dai, Travis Spriggs, Yetunde Ogunbolude, Erika Beaton, Michelle Sanders, Raghuveera K Goel, Keith Bonham, Kiven E Lukong
The triple-negative breast cancer subtype is highly aggressive and has no defined therapeutic target. Fyn-related kinase (FRK) is a non-receptor tyrosine kinase, reported to be downregulated in breast cancer and gliomas, where it is suggested to have tumor suppressor activity. We examined the expression profile of FRK in a panel of 40 breast cancer cells representing all the major subtypes, as well as in 4 non-malignant mammary epithelial cell lines. We found that FRK expression was significantly repressed in a proportion of basal B breast cancer cell lines...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/27917408/prostate-specific-membrane-antigen-targeted-polymersomes-for-delivering-mocetinostat-and-docetaxel-to-prostate-cancer-cell-spheroids
#11
Fataneh Karandish, Manas K Haldar, Seungyong You, Amanda E Brooks, Benjamin D Brooks, Bin Guo, Yongki Choi, Sanku Mallik
Prostate cancer cells overexpress the prostate-specific membrane antigen (PSMA) receptors on the surface. Targeting the PSMA receptor creates a unique opportunity for drug delivery. Docetaxel is a Food and Drug Administration-approved drug for treating metastatic and androgen-independent prostate cancer, and mocetinostat is a potent inhibitor of class I histone deacetylases. In this study, we prepared reduction-sensitive polymersomes presenting folic acid on the surface and encapsulating either docetaxel or mocetinostat...
November 30, 2016: ACS Omega
https://www.readbyqxmd.com/read/27863907/evidence-of-epigenetic-tags-in-cardiac-fibrosis
#12
REVIEW
Vincenzo Grimaldi, Maria Rosaria De Pascale, Alberto Zullo, Andrea Soricelli, Teresa Infante, Francesco Paolo Mancini, Claudio Napoli
In cardiac fibrosis, following an injury or a stress, non-functional fibrotic tissue substitutes normal myocardium, thus leading to progressive heart failure. Activated fibroblasts are principal determinants of cardiac fibrosis by producing excessive fibrotic extracellular matrix and causing hypertrophy of cardiomyocytes. Epigenetic changes, such as DNA methylation, histone modifications, and miRNAs have been involved in these mechanisms. Therefore, there is a strong interest in reverting such epigenetic transformations in order to arrest myocardial fibrotic degeneration...
February 2017: Journal of Cardiology
https://www.readbyqxmd.com/read/27666412/colorectal-cancer-cell-derived-microrna200-modulates-the-resistance-of-adjacent-blood-endothelial-barriers-in%C3%A2-vitro
#13
Silvio Holzner, Daniel Senfter, Serena Stadler, Anna Staribacher, Chi Huu Nguyen, Anna Gaggl, Silvana Geleff, Nicole Huttary, Sigurd Krieger, Walter Jäger, Helmut Dolznig, Robert M Mader, Georg Krupitza
Since cancer cells, when grown as spheroids, display drug sensitivity and radiation resistance patterns such as seen in vivo we recently established a three‑dimensional (3D) in vitro model recapitulating colorectal cancer (CRC)-triggered lymphatic endothelial cell (LEC)‑barrier breaching to study mechanisms of intra‑/extravasation. CRC metastasizes not only through lymphatics but also through blood vessels and here we extend the 3D model to the interaction of blood endothelial cells (BECs) with naïve and 5‑fluorouracil (5‑FU)‑resistant CRC CCL227 cells...
November 2016: Oncology Reports
https://www.readbyqxmd.com/read/27551531/an-epithelial-marker-promoter-induction-screen-identifies-histone-deacetylase-inhibitors-to-restore-epithelial-differentiation-and-abolishes-anchorage-independence-growth-in-cancers
#14
H M Tang, K T Kuay, P F Koh, M Asad, T Z Tan, V Y Chung, S C Lee, J P Thiery, Ry-J Huang
Epithelial-mesenchymal transition (EMT), a crucial mechanism in development, mediates aggressiveness during carcinoma progression and therapeutic refractoriness. The reversibility of EMT makes it an attractive strategy in designing novel therapeutic approaches. Therefore, drug discovery pipelines for EMT reversal are in need to discover emerging classes of compounds. Here, we outline a pre-clinical drug screening platform for EMT reversal that consists of three phases of drug discovery and validation. From the Phase 1 epithelial marker promoter induction (EpI) screen on a library consisting of compounds being approved by Food and Drug Administration (FDA), Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), is identified to exert EMT reversal effects by restoring the expression of an epithelial marker, E-cadherin...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/27551526/class-i-hdac-inhibitor-mocetinostat-induces-apoptosis-by-activation-of-mir-31-expression-and-suppression-of-e2f6
#15
Q Zhang, M Sun, S Zhou, B Guo
The class I selective inhibitor of the histone deacetylases, mocetinostat, has promising antitumor activities in both preclinical studies and the clinical trials. To understand how mocetinostat induces apoptosis, we examined the effects of mocetinostat on miR-31, a proapoptotic microRNA that was previously found to be epigenetically silenced in prostate cancer. We found that miR-31 was significantly upregulated by mocetinostat in prostate cancer cells. Antiapoptotic protein E2F6, the target of miR-31, was decreased by mocetinostat treatment...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/27499916/hr23b-expression-is-a-potential-predictive-biomarker-for-hdac-inhibitor-treatment-in-mesenchymal-tumours-and-is-associated-with-response-to-vorinostat
#16
Michaela Angelika Ihle, Sabine Merkelbach-Bruse, Wolfgang Hartmann, Sebastian Bauer, Nancy Ratner, Hiroshi Sonobe, Jun Nishio, Olle Larsson, Pierre Åman, Florence Pedeutour, Takahiro Taguchi, Eva Wardelmann, Reinhard Buettner, Hans-Ulrich Schildhaus
Histone deacetylases (HDAC) are key players in epigenetic regulation of gene expression and HDAC inhibitor (HDACi) treatment seems to be a promising anticancer therapy in many human tumours, including soft tissue sarcomas. HR23b has been shown to be a potential biomarker for sensitivity to HDACi therapy in cutaneous T-cell lymphoma and hepatocellular carcinoma. We aimed to evaluate HR23b as a candidate biomarker for HDACi response in sarcomas and gastrointestinal stromal tumours (GIST). Therefore, HR23b expression was analysed comprehensively by western blot in sarcoma and GIST cell lines covering all major clinically relevant subtypes...
April 2016: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/27278287/histone-deacetyltransferase-inhibitors-trichostatin-a-and-mocetinostat-differentially-regulate-mmp9-il-18-and-reck-expression-and-attenuate-angiotensin-ii-induced-cardiac-fibroblast-migration-and-proliferation
#17
Naveen K Somanna, Anthony J Valente, Maike Krenz, Kerry S McDonald, Yusuke Higashi, Makoto Noda, Bysani Chandrasekar
Histone acetylation/deacetylation plays a key role in the epigenetic regulation of multiple pro-fibrotic genes. Here we investigated the effects of histone deacetyltransferase (HDAC) inhibition on angiotensin (Ang)-II-induced pro-fibrotic changes in adult mouse cardiac fibroblasts (CF). CF express class I HDACs 1 and 2, and Ang-II induces their activation. Notably, silencing HDAC1 or HDAC2 attenuated Ang-II induced CF proliferation and migration. Under basal conditions, HDAC1 dimerizes with HDAC2 in CF and Ang-II reversed this interaction...
October 2016: Hypertension Research: Official Journal of the Japanese Society of Hypertension
https://www.readbyqxmd.com/read/27249803/profile-of-class-i-histone-deacetylases-hdac-by-human-dendritic-cells-after-alcohol-consumption-and-in-vitro-alcohol-treatment-and-their-implication-in-oxidative-stress-role-of-hdac-inhibitors-trichostatin-a-and-mocetinostat
#18
Marisela Agudelo, Gloria Figueroa, Tiyash Parira, Adriana Yndart, Karla Muñoz, Venkata Atluri, Thangavel Samikkannu, Madhavan P Nair
Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of histone deacetylases (HDACs) on alcohol-induced oxidative stress of human primary monocyte-derived dendritic cells (MDDCs) has not been elucidated. In the current study, we took a novel approach combining ex vivo, in vitro and in silico analyses to elucidate the mechanisms of alcohol-induced oxidative stress and role of HDACs in the periphery. ex vivo and in vitro analyses of alcohol-modulation of class I HDACs and activity by MDDCs from self-reported alcohol users and non-alcohol users was performed...
2016: PloS One
https://www.readbyqxmd.com/read/26721445/hdac-inhibitors-induce-global-changes-in-histone-lysine-and-arginine-methylation-and-alter-expression-of-lysine-demethylases
#19
Ryan Lillico, Marina Gomez Sobral, Nicholas Stesco, Ted M Lakowski
Histone deacetylase (HDAC) inhibitors are cancer treatments that inhibit the removal of the epigenetic modification acetyllysine on histones, resulting in altered gene expression. Such changes in expression may influence other histone epigenetic modifications. We describe a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify lysine acetylation and methylation and arginine methylation on histones extracted from cultured cells treated with HDAC inhibitors. The HDAC inhibitors vorinostat, mocetinostat and entinostat induced 400-600% hyperacetylation in HEK 293 and K562 cells...
February 5, 2016: Journal of Proteomics
https://www.readbyqxmd.com/read/26464683/metabolic-changes-in-rats-after-intragastric-administration-of-mgcd0103-mocetinostat-a-hdac-class-i-inhibitor
#20
Qingwei Zhang, Haiya Wu, Congcong Wen, Fa Sun, Xuezhi Yang, Lufeng Hu
MGCD0103, an isotype-selective HDACi, has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In this study, we developed a serum metabolomic method based on gas chromatography-mass spectrometry (GC-MS) to evaluate the effect of intragastric administration of MGCD0103 on rats. The MGCD0103 group rats were given 20, 40, 80 mg/kg of MGCD0103 by intragastric administration each day for 7 days. Pattern recognition analysis, including both principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) revealed that intragastric administration of MGCD0103 induced metabolic perturbations...
2015: International Journal of Clinical and Experimental Pathology
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