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stephen baylin

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https://www.readbyqxmd.com/read/29615458/an-effective-epigenetic-parp-inhibitor-combination-therapy-for-breast-and-ovarian-cancers-independent-of-brca-mutations
#1
Nicholas Pulliam, Fang Fang, Ali R Ozes, Jessica Tang, Adeoluwa Adewuyi, Harold Keer, John Lyons, Stephen B Baylin, Daniela Matei, Harikrishna Nakshatri, Feyruz V Rassool, Kathy D Miller, Kenneth P Nephew
Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status...
July 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29438699/dna-methylation-patterns-separate-senescence-from-transformation-potential-and-indicate-cancer-risk
#2
Wenbing Xie, Ioannis Kagiampakis, Lixia Pan, Yang W Zhang, Lauren Murphy, Yong Tao, Xiangqian Kong, Byunghak Kang, Limin Xia, Filipe L F Carvalho, Subhojit Sen, Ray-Whay Chiu Yen, Cynthia A Zahnow, Nita Ahuja, Stephen B Baylin, Hariharan Easwaran
Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence-associated hypermethylation mainly involves metabolic regulators and appears early in proliferating "near-senescent" cells, which can be immortalized but are refractory to transformation...
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29381856/biochemical-studies-and-molecular-dynamic-simulations-reveal-the-molecular-basis-of-conformational-changes-in-dna-methyltransferase-1
#3
Fei Ye, Xiangqian Kong, Hao Zhang, Yan Liu, Zhiyuan Shao, Jia Jin, Yi Cai, Rukang Zhang, Linjuan Li, Yang W Zhang, Yu-Chih Liu, Chenhua Zhang, Wenbing Xie, Kunqian Yu, Hong Ding, Kehao Zhao, Shijie Chen, Hualiang Jiang, Stephen B Baylin, Cheng Luo
DNA methyltransferase-1 (DNMT1) plays a crucial role in the maintenance of genomic methylation patterns. The crystal structure of DNMT1 was determined in two different states in which the helix that follows the catalytic loop was either kinked (designated helix-kinked) or well folded (designated helix-straight state). Here, we show that the proper structural transition between these two states is required for DNMT1 activity. The mutations of N1248A and R1279D, which did not affect interactions between DNMT1 and substrates or cofactors, allosterically reduced enzymatic activities in vitro by decreasing kcat / Km for AdoMet...
March 16, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29367758/the-tumor-suppressor-hic1-maintains-chromosomal-stability-independent-of-tp53
#4
Anette Szczepny, Kirstyn Carey, Lisa McKenzie, W Samantha N Jayasekara, Fernando Rossello, Alvaro Gonzalez-Rajal, Andrew S McCaw, Dean Popovski, Die Wang, Anthony J Sadler, Annabelle Mahar, Prudence A Russell, Gavin Wright, Rachael A McCloy, Daniel J Garama, Daniel J Gough, Stephen B Baylin, Andrew Burgess, Jason E Cain, D Neil Watkins
Hypermethylated-in-Cancer 1 (Hic1) is a tumor suppressor gene frequently inactivated by epigenetic silencing and loss-of-heterozygosity in a broad range of cancers. Loss of HIC1, a sequence-specific zinc finger transcriptional repressor, results in deregulation of genes that promote a malignant phenotype in a lineage-specific manner. In particular, upregulation of the HIC1 target gene SIRT1, a histone deacetylase, can promote tumor growth by inactivating TP53. An alternate line of evidence suggests that HIC1 can promote the repair of DNA double strand breaks through an interaction with MTA1, a component of the nucleosome remodeling and deacetylase (NuRD) complex...
January 25, 2018: Oncogene
https://www.readbyqxmd.com/read/29282222/a-kdm5-inhibitor-increases-global-h3k4-trimethylation-occupancy-and-enhances-the-biological-efficacy-of-5-aza-2-deoxycytidine
#5
Benjamin R Leadem, Ioannis Kagiampakis, Catherine Wilson, Tommy K Cheung, David Arnott, Patrick Trojer, Marie Classon, Hariharan Easwaran, Stephen B Baylin
The H3K4 demethylase KDM5B is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here, we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA-demethylating agent 5-aza-2'-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes...
March 1, 2018: Cancer Research
https://www.readbyqxmd.com/read/29203668/epigenetic-therapy-activates-type-i-interferon-signaling-in-murine-ovarian-cancer-to-reduce-immunosuppression-and-tumor-burden
#6
Meredith L Stone, Katherine B Chiappinelli, Huili Li, Lauren M Murphy, Meghan E Travers, Michael J Topper, Dimitrios Mathios, Michael Lim, Ie-Ming Shih, Tian-Li Wang, Chien-Fu Hung, Vipul Bhargava, Karla R Wiehagen, Glenn S Cowley, Kurtis E Bachman, Reiner Strick, Pamela L Strissel, Stephen B Baylin, Cynthia A Zahnow
Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy...
December 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29195073/epigenetic-therapy-ties-myc-depletion-to-reversing-immune-evasion-and-treating-lung-cancer
#7
Michael J Topper, Michelle Vaz, Katherine B Chiappinelli, Christina E DeStefano Shields, Noushin Niknafs, Ray-Whay Chiu Yen, Alyssa Wenzel, Jessica Hicks, Matthew Ballew, Meredith Stone, Phuoc T Tran, Cynthia A Zahnow, Matthew D Hellmann, Valsamo Anagnostou, Pamela L Strissel, Reiner Strick, Victor E Velculescu, Stephen B Baylin
Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/28898697/chronic-cigarette-smoke-induced-epigenomic-changes-precede-sensitization-of-bronchial-epithelial-cells-to-single-step-transformation-by-kras-mutations
#8
Michelle Vaz, Stephen Y Hwang, Ioannis Kagiampakis, Jillian Phallen, Ashwini Patil, Heather M O'Hagan, Lauren Murphy, Cynthia A Zahnow, Edward Gabrielson, Victor E Velculescu, Hariharan P Easwaran, Stephen B Baylin
We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer...
September 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28622390/inhibiting-dna-methylation-activates-cancer-testis-antigens-and-expression-of-the-antigen-processing-and-presentation-machinery-in-colon-and-ovarian-cancer-cells
#9
Cornelia Siebenkäs, Katherine B Chiappinelli, Angela A Guzzetta, Anup Sharma, Jana Jeschke, Rajita Vatapalli, Stephen B Baylin, Nita Ahuja
Innovative therapies for solid tumors are urgently needed. Recently, therapies that harness the host immune system to fight cancer cells have successfully treated a subset of patients with solid tumors. These responses have been strong and durable but observed in subsets of patients. Work from our group and others has shown that epigenetic therapy, specifically inhibiting the silencing DNA methylation mark, activates immune signaling in tumor cells and can sensitize to immune therapy in murine models. Here we show that colon and ovarian cancer cell lines exhibit lower expression of transcripts involved in antigen processing and presentation to immune cells compared to normal tissues...
2017: PloS One
https://www.readbyqxmd.com/read/28486105/chd4-has-oncogenic-functions-in-initiating-and-maintaining-epigenetic-suppression-of-multiple-tumor-suppressor-genes
#10
Limin Xia, Wenjie Huang, Marina Bellani, Michael M Seidman, Kaichun Wu, Daiming Fan, Yongzhan Nie, Yi Cai, Yang W Zhang, Li-Rong Yu, Huili Li, Cynthia A Zahnow, Wenbing Xie, Ray-Whay Chiu Yen, Feyruz V Rassool, Stephen B Baylin
An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks...
May 8, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28445481/hypomethylating-agents-synergize-with-irinotecan-to-improve-response-to-chemotherapy-in-colorectal-cancer-cells
#11
Anup Sharma, Rajita Vatapalli, Eihab Abdelfatah, K Wyatt McMahon, Zachary Kerner, Angela A Guzzetta, Jasvinder Singh, Cynthia Zahnow, Stephen B Baylin, Sashidhar Yerram, Yue Hu, Nilofer Azad, Nita Ahuja
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. In the metastatic setting, the majority of patients respond to initial therapies but eventually develop resistance and progress. In this study, we test the hypothesis that priming with epigenetic therapy sensitizes CRC cell lines, which were previously resistant to subsequent chemotherapeutic agents. When multiple CRC cell lines are first exposed to 500 nM of the DNA demethylating agent, 5-aza-cytidine (AZA) in-vitro, and the cells then established as in-vivo xenografts in untreated NOD-SCID mice; there is an enhanced response to cytotoxic chemotherapy with agents commonly used in CRC treatment...
2017: PloS One
https://www.readbyqxmd.com/read/28407701/correction-a-new-immunohistochemistry-prognostic-score-ips-for-recurrence-and-survival-in-resected-pancreatic-neuroendocrine-tumors-pannet
#12
Antonio Viúdez, Filipe L F Carvalho, Zahra Maleki, Marianna Zahurak, Daniel Laheru, Alejandro Stark, Nilofer S Azad, Christopher L Wolfgang, Stephen Baylin, James G Herman, Ana De Jesus-Acosta
No abstract text is available yet for this article.
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28388418/inhibiting-dna-methylation-causes-an-interferon-response-in-cancer-via-dsrna-including-endogenous-retroviruses
#13
Katherine B Chiappinelli, Pamela L Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S Rote, Leslie M Cope, Alexandra Snyder, Vladimir Makarov, Sadna Budhu, Dennis J Slamon, Jedd D Wolchok, Drew M Pardoll, Matthias W Beckmann, Cynthia A Zahnow, Taha Merghoub, Timothy A Chan, Stephen B Baylin, Reiner Strick
No abstract text is available yet for this article.
April 6, 2017: Cell
https://www.readbyqxmd.com/read/28202634/dietary-patterns-are-associated-with-metabolic-outcomes-among-adult-samoans-in-a-cross-sectional-study
#14
Dongqing Wang, Nicola L Hawley, Avery A Thompson, Viali Lameko, Muagatutia Sefuiva Reupena, Stephen T McGarvey, Ana Baylin
Background: The Samoan population has been undergoing a nutrition transition toward more imported and processed foods and a more sedentary lifestyle. Objectives: We aimed to identify dietary patterns in Samoa and to evaluate their associations with metabolic outcomes. Methods: The sample of this cross-sectional study includes 2774 Samoan adults recruited in 2010 (1104 with metabolic syndrome compared with 1670 without). Principal component analysis on food items from a 104-item food-frequency questionnaire was used to identify dietary patterns...
April 2017: Journal of Nutrition
https://www.readbyqxmd.com/read/28186961/combination-epigenetic-therapy-in-metastatic-colorectal-cancer-mcrc-with-subcutaneous-5-azacitidine-and-entinostat-a-phase-2-consortium-stand-up-2-cancer-study
#15
MULTICENTER STUDY
Nilofer S Azad, Anthony El-Khoueiry, Jun Yin, Ann L Oberg, Patrick Flynn, Douglas Adkins, Anup Sharma, Daniel J Weisenberger, Thomas Brown, Prakriti Medvari, Peter A Jones, Hariharan Easwaran, Ihab Kamel, Nathan Bahary, George Kim, Joel Picus, Henry C Pitot, Charles Erlichman, Ross Donehower, Hui Shen, Peter W Laird, Richard Piekarz, Stephen Baylin, Nita Ahuja
PURPOSE: Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. EXPERIMENTAL DESIGN: We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28107650/acetylation-enhances-tet2-function-in-protecting-against-abnormal-dna-methylation-during-oxidative-stress
#16
Yang W Zhang, Zhihong Wang, Wenbing Xie, Yi Cai, Limin Xia, Hariharan Easwaran, Jianjun Luo, Ray-Whay Chiu Yen, Yana Li, Stephen B Baylin
TET proteins, by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are hypothesized, but not directly shown, to protect promoter CpG islands (CGIs) against abnormal DNA methylation (DNAm) in cancer. We define such a protective role linked to DNA damage from oxidative stress (OS) known to induce this abnormality. TET2 removes aberrant DNAm during OS through interacting with DNA methyltransferases (DNMTs) in a "Yin-Yang" complex targeted to chromatin and enhanced by p300 mediated TET2 acetylation...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28031159/evolution-of-neoantigen-landscape-during-immune-checkpoint-blockade-in-non-small-cell-lung-cancer
#17
Valsamo Anagnostou, Kellie N Smith, Patrick M Forde, Noushin Niknafs, Rohit Bhattacharya, James White, Theresa Zhang, Vilmos Adleff, Jillian Phallen, Neha Wali, Carolyn Hruban, Violeta B Guthrie, Kristen Rodgers, Jarushka Naidoo, Hyunseok Kang, William Sharfman, Christos Georgiades, Franco Verde, Peter Illei, Qing Kay Li, Edward Gabrielson, Malcolm V Brock, Cynthia A Zahnow, Stephen B Baylin, Robert B Scharpf, Julie R Brahmer, Rachel Karchin, Drew M Pardoll, Victor E Velculescu
Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones...
March 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27979916/combination-epigenetic-therapy-in-advanced-breast-cancer-with-5-azacitidine-and-entinostat-a-phase-ii-national-cancer-institute-stand-up-to-cancer-study
#18
Roisin M Connolly, Huili Li, Rachel C Jankowitz, Zhe Zhang, Michelle A Rudek, Stacie C Jeter, Shannon A Slater, Penny Powers, Antonio C Wolff, John H Fetting, Adam Brufsky, Richard Piekarz, Nita Ahuja, Peter W Laird, Hui Shen, Daniel J Weisenberger, Leslie Cope, James G Herman, George Somlo, Agustin A Garcia, Peter A Jones, Stephen B Baylin, Nancy E Davidson, Cynthia A Zahnow, Vered Stearns
Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Experimental Design: Patients received 5-azacitidine 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3, 10) on a 28-day cycle...
June 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27880934/tumors-with-unmethylated-mlh1-and-the-cpg-island-methylator-phenotype-are-associated-with-a-poor-prognosis-in-stage-ii-colorectal-cancer-patients
#19
Tao Fu, Yanliang Liu, Kai Li, Weiwei Wan, Emmanouil P Pappou, Christine A Iacobuzio-Donahue, Zachary Kerner, Stephen B Baylin, Christopher L Wolfgang, Nita Ahuja
We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status. Here, we tested the prognostic value of this model in stage II colorectal cancer (CRC) patients. Tumors were assigned to CIMP+/MLH1-unmethylated (MLH1-U), CIMP+/MLH1-methylated (MLH1-M), CIMP-/MLH1-U, or CIMP-/MLH1-M groups. Age, tumor location, lymphovascular invasion, and mucin production differed among the four patient subgroups, and CIMP+/MLH1-U tumors were more likely to have lymphovascular invasion and mucin production...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27729459/early-detection-of-lung-cancer-using-dna-promoter-hypermethylation-in-plasma-and-sputum
#20
Alicia Hulbert, Ignacio Jusue-Torres, Alejandro Stark, Chen Chen, Kristen Rodgers, Beverly Lee, Candace Griffin, Andrew Yang, Peng Huang, John Wrangle, Steven A Belinsky, Tza-Huei Wang, Stephen C Yang, Stephen B Baylin, Malcolm V Brock, James G Herman
Purpose: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer-specific gene panel to detect DNA methylation in sputum and plasma.Experimental Design: This is a case-control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (n = 150) had pathologic confirmation of node-negative (stages I and IIA) non-small cell lung cancer. Controls (n = 60) had non-cancer diagnoses...
April 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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