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21 results on '"Bradner J.E."'

1. Supplemental Figure S4 from Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase Inhibitors by Multimodality Molecular Imaging in Living Subjects

Author

Chan, C.T., primary, Qi, J., primary, Smith, W., primary, Paranol, R., primary, Mazitschek, R., primary, West, N., primary, Reeves, R., primary, Chiosis, G., primary, Schreiber, S.L., primary, Bradner, J.E., primary, Paulmurugan, R., primary, and Gambhir, S.S., primary

Published
2023
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2. Supplemental Methods from Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase Inhibitors by Multimodality Molecular Imaging in Living Subjects

Author

Chan, C.T., primary, Qi, J., primary, Smith, W., primary, Paranol, R., primary, Mazitschek, R., primary, West, N., primary, Reeves, R., primary, Chiosis, G., primary, Schreiber, S.L., primary, Bradner, J.E., primary, Paulmurugan, R., primary, and Gambhir, S.S., primary

Published
2023
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3. Supplemental Table S1 from Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase Inhibitors by Multimodality Molecular Imaging in Living Subjects

Author

Chan, C.T., primary, Qi, J., primary, Smith, W., primary, Paranol, R., primary, Mazitschek, R., primary, West, N., primary, Reeves, R., primary, Chiosis, G., primary, Schreiber, S.L., primary, Bradner, J.E., primary, Paulmurugan, R., primary, and Gambhir, S.S., primary

Published
2023
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4. Supplemental Figure Legends from Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase Inhibitors by Multimodality Molecular Imaging in Living Subjects

Author

Chan, C.T., primary, Qi, J., primary, Smith, W., primary, Paranol, R., primary, Mazitschek, R., primary, West, N., primary, Reeves, R., primary, Chiosis, G., primary, Schreiber, S.L., primary, Bradner, J.E., primary, Paulmurugan, R., primary, and Gambhir, S.S., primary

Published
2023
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7. Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer

Author

King, M.P., Pfeiffer, H.K., Shadel, G.S., Gaballa, M.R., Cotney, J.L., Chodosh, L.A., Shen, C., Sharma, S.D., McMahon, S.B., Arnold, J.J., Eischen, C.M., Oran, A.R., Bradner, J.E., Mascioli, K., Thompson, J.E., Vakoc, C.R., Seidel, H.E., Kaplan, J., Mellert, H.S., Adams, C.M., Cameron, C.E., Martinez-Outschoorn, U.E., Gennaro, V.J., Zhang, X.-Y., and Rigoutsos, I.

Abstract

Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production. Fortuitously, MYC-dependent tumor cell death can be induced by inhibiting the mitochondrial gene expression pathway using a variety of strategies, including treatment with FDA-approved antibiotics. In vivo studies using a mouse model of Burkitt's Lymphoma provide pre-clinical evidence that these antibiotics can successfully block progression of MYC-dependent tumors.

Published
2016
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8. BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1.

Author

Johnstone R.W., Hogg S.J., Vervoort S.J., Deswal S., Ott C.J., Li J., Shortt J., Cluse L.A., Beavis P.A., Darcy P.K., Martin B.P., Spencer A., Traunbauer A.K., Sadovnik I., Bauer K., Valent P., Bradner J.E., Zuber J., Johnstone R.W., Hogg S.J., Vervoort S.J., Deswal S., Ott C.J., Li J., Shortt J., Cluse L.A., Beavis P.A., Darcy P.K., Martin B.P., Spencer A., Traunbauer A.K., Sadovnik I., Bauer K., Valent P., Bradner J.E., and Zuber J.

Abstract

BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-gamma) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274.Copyright © 2017 The Author(s)

Published
2017

9. A chemical probe toolbox for dissecting the cancer epigenome.

Author

Ott C.J., Bradner J.E., Johnstone R.W., Shortt J., Ott C.J., Bradner J.E., Johnstone R.W., and Shortt J.

Abstract

Cancer cell hallmarks are underpinned by transcriptional programmes operating in the context of a dynamic and complicit epigenomic environment. Somatic alterations of chromatin modifiers are among the most prevalent cancer perturbations. There is a pressing need for targeted chemical probes to dissect these complex, interconnected gene regulatory circuits. Validated chemical probes empower mechanistic research while providing the pharmacological proof of concept that is required to translate drug-like derivatives into therapy for cancer patients. In this Review, we describe chemical probe development for epigenomic effector proteins that are linked to cancer pathogenesis. By annotating these reagents, we aim to share our perspectives on an informative 'epigenomic toolbox' of broad utility to the research community.Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature.

Published
2017

10. BET inhibition induces apoptosis in aggressive B-cell lymphoma via epigenetic regulation of BCL-2 family members.

Author

Johnstone R.W., Gregory G.P., Lefebure M., Vidacs E., Tothill R.W., Bradner J.E., Shortt J., Hogg S.J., Newbold A., Vervoort S.J., Cluse L.A., Martin B.P., Johnstone R.W., Gregory G.P., Lefebure M., Vidacs E., Tothill R.W., Bradner J.E., Shortt J., Hogg S.J., Newbold A., Vervoort S.J., Cluse L.A., and Martin B.P.

Abstract

Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a keymechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Emu-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of proapoptotic (Bim) and antiapoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Emu-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1 resistance phenotype. These studies provide important information on mechanisms of apoptosis induction and resistance to BETinhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas.Copyright © 2016 American Association for Cancer Research.

Published
2016

11. Synthesis and HDAC inhibitory activity of isosteric thiazoline-oxazole largazole analogs

Author

Wiest, O., Estiu, G., Smith, W.B., Bradner, J.E., Williams, R.M., Paranal, R., Guerra-Bubb, J.M., and Bowers, A.A.

Subjects
inorganic chemicals
Abstract

The synthesis of an isosteric analog of the natural product and HDAC inhibitor largazole is described. The sulfur atom in the thizaole ring of the natural product has been replaced with an oxygen atom, constituting an oxazole ring. The biochemical activity and cytotoxicity of this species is described.

Published
2013
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13. Synthesis and conformation-activity relationships of the peptide isosteres of FK228 and largazole

Author

West, N., Williams, R.M., Wiest, O., Greshook, T.J., Schreiber, S.L., Bowers, A.A., Estiu, G., and Bradner, J.E.

Abstract

The peptide isosteres (10 and 11) of the naturally occurring and potent histone deacetylase (HDAC) Inhibitors FK228 and largazole have been synthesized and evaluated side-by-side with FK228, largazole, and SAHA for inhibition of the class I HDACs 1, 2, 3, and 6.

Published
2009
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14. Total synthesis and biological mode of action of largazole: A potent class I histone deacetylase inhibitor

Author

Schreiber, S.L., Bowers, A., Bradner, J.E., Williams, R.M., West, N., and Taunton, J.

Abstract

The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite 2, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and 2 have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances.

Published
2008
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15. Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase Inhibitors by Multimodality Molecular Imaging in Living Subjects

Author

Chan, C.T., primary, Qi, J., additional, Smith, W., additional, Paranol, R., additional, Mazitschek, R., additional, West, N., additional, Reeves, R., additional, Chiosis, G., additional, Schreiber, S.L., additional, Bradner, J.E., additional, Paulmurugan, R., additional, and Gambhir, S.S., additional

Published
2014
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19. High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program

Author

Sudeepa Syamala, Leigh Ellis, R. Jeffrey Karnes, Stefano Cacciatore, Ashley E. Ross, Jorge E. Chavarro, Robert B. Den, Myles Brown, Giorgia Zadra, Mandeep Takhar, Charles Y. Lin, David P. Labbé, Ericka M. Ebot, Meng Yang, Anthony V. DʼAmico, Philip W. Kantoff, Habiba Elfandy, Stephen J. Freedland, Jonathan Lehrer, Jacob D. Jaffe, Lorelei A. Mucci, James E. Bradner, Amanda L. Creech, Daniel E. Spratt, Mohammed Alshalalfa, Edward M. Schaeffer, Jaime M. Reyes, Nicholas Erho, Edward D. Karoly, Massimo Loda, Francesca Giunchi, Elai Davicioni, Ewan A. Gibb, Michelangelo Fiorentino, Labbe D.P., Zadra G., Yang M., Reyes J.M., Lin C.Y., Cacciatore S., Ebot E.M., Creech A.L., Giunchi F., Fiorentino M., Elfandy H., Syamala S., Karoly E.D., Alshalalfa M., Erho N., Ross A., Schaeffer E.M., Gibb E.A., Takhar M., Den R.B., Lehrer J., Karnes R.J., Freedland S.J., Davicioni E., Spratt D.E., Ellis L., Jaffe J.D., D'Amico A.V., Kantoff P.W., Bradner J.E., Mucci L.A., Chavarro J.E., Loda M., and Brown M.

Subjects
0301 basic medicine, Male, Saturated fat, Transgene, Science, General Physics and Astronomy, Mice, Transgenic, Diet, High-Fat, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Cell Line, Tumor, Metabolome, Medicine, Animals, Humans, lcsh:Science, Gene, Aged, Cell Proliferation, 2. Zero hunger, Regulation of gene expression, Multidisciplinary, biology, business.industry, prostate cancer, metabolism, Prostatic Neoplasms, General Chemistry, Middle Aged, medicine.disease, Obesity, 3. Good health, Tumor Burden, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Histone, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Disease Progression, lcsh:Q, business
Abstract

Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet.

Published
2018

20. CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

Author

Levi D. Ali, Gabriela Alexe, Barbara A. Weir, Amanda Balboni Iniguez, Liying Chen, Sasha Pantel, James E. Bradner, Carol J. Thiele, Jun Qi, W. Clay Gustafson, Nicole Nasholm, Rakela Lubonja, Norris Lam, David E. Root, Guozhi Jiang, William C. Hahn, Amy Goodale, Aviad Tsherniak, Amy Saur Conway, Linda Ross, Veronica Veschi, Charles W. M. Roberts, John M. Krill-Burger, Todd R. Golub, Francisca Vazquez, Glenn S. Cowley, William A. Weiss, Yenarae Lee, William F. Harrington, Neekesh V. Dharia, Emily Jue Wang, Kimberly Stegmaier, Robin M. Meyers, Chen L., Alexe G., Dharia N.V., Ross L., Iniguez A.B., Conway A.S., Wang E.J., Veschi V., Lam N., Qi J., Clay Gustafson W., Nasholm N., Vazquez F., Weir B.A., Cowley G.S., Ali L.D., Pantel S., Jiang G., Harrington W.F., Lee Y., Goodale A., Lubonja R., Krill-Burger J.M., Meyers R.M., Tsherniak A., Root D.E., Bradner J.E., Golub T.R., Roberts C.W.M., Hahn W.C., Weiss W.A., Thiele C.J., and Stegmaier K.

Subjects
0301 basic medicine, Cellular differentiation, Medical and Health Sciences, Neuroblastoma, SUZ12, Oncogene MYCN, CRISPR-Cas System, Cancer, Pediatric, Neurons, N-Myc Proto-Oncogene Protein, Tumor, EZH2, Epigenetic, Cell Differentiation, General Medicine, Up-Regulation, Gene Expression Regulation, Neoplastic, Oncology, 5.1 Pharmaceuticals, Epigenetics, Development of treatments and therapeutic interventions, Human, Research Article, Pediatric Research Initiative, Pediatric Cancer, Immunology, macromolecular substances, Biology, Cell Line, 03 medical and health sciences, Rare Diseases, Cell Line, Tumor, medicine, Genetics, Humans, Enhancer of Zeste Homolog 2 Protein, Transcription factor, neoplasms, Neoplastic, Human Genome, Neurosciences, Gene Amplification, Neuron, medicine.disease, 030104 developmental biology, Gene Expression Regulation, Cancer research, Histone deacetylase, CRISPR-Cas Systems
Abstract

Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

Published
2016

21. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism

Author

Stéphanie Puget, Mariarita Santi, Daniel C. Bowers, Cynthia Hawkins, Rosemary E. Henn, Laura M. Urbanski, Jeremiah Wala, Mélanie Pagès, Azra H. Ligon, Anna Maria Buccoliero, Peleg M. Horowitz, Phillip B. Storm, Mirko Scagnet, Liliana Goumnerova, Matthew D. Ducar, Kristine Pelton, Pascale Varlet, Uri Tabori, Sabine Mueller, Pratiti Bandopadhayay, Yun Jee Kang, Rameen Beroukhim, Joanna J. Phillips, Adam C. Resnick, Payal Jain, Brenton R. Paolella, László Bognár, Mark W. Kieran, David S. Knoff, Yuankun Zhu, Rhamy Zeid, Shakti Ramkissoon, Charles G. Eberhart, Hayley Malkin, Adam Tracy, Katie Boucher, Amanda Silva, Lori A. Ramkissoon, Adrianne Gladden-Young, Keith L. Ligon, Nada Jabado, Jacques Grill, Daphne A. Haas-Kogan, Sandro Santagata, James E. Bradner, Charles D. Stiles, Alexander J. Federation, Harry J. Han, Almos Klekner, Angela J. Waanders, Sara Seepo, Ryan O’Rourke, Paul Van Hummelen, Namrata Choudhari, D. Ashley Hill, Fausto J. Rodriguez, Caterina Giannini, William J. Gibson, Alon Goren, Peter C. Burger, Guillaume Bergthold, Steven E. Schumacher, Bandopadhayay P., Ramkissoon L.A., Jain P., Bergthold G., Wala J., Zeid R., Schumacher S.E., Urbanski L., O'Rourke R., Gibson W.J., Pelton K., Ramkissoon S.H., Han H.J., Zhu Y., Choudhari N., Silva A., Boucher K., Henn R.E., Kang Y.J., Knoff D., Paolella B.R., Gladden-Young A., Varlet P., Pages M., Horowitz P.M., Federation A., Malkin H., Tracy A.A., Seepo S., Ducar M., Van Hummelen P., Santi M., Buccoliero A.M., Scagnet M., Bowers D.C., Giannini C., Puget S., Hawkins C., Tabori U., Klekner A., Bognar L., Burger P.C., Eberhart C., Rodriguez F.J., Hill D.A., Mueller S., Haas-Kogan D.A., Phillips J.J., Santagata S., Stiles C.D., Bradner J.E., Jabado N., Goren A., Grill J., Ligon A.H., Goumnerova L., Waanders A.J., Storm P.B., Kieran M.W., Ligon K.L., Beroukhim R., and Resnick A.C.

Subjects
0301 basic medicine, Oncogene Proteins, Fusion, Carcinogenesis, Angiocentric Glioma, Biology, medicine.disease_cause, Article, Oncogene Proteins v-myb, 03 medical and health sciences, Glioma, Cell Line, Tumor, Genetics, medicine, Humans, MYB, Exome, Epigenetics, Child, Carcinogenesi, Gene Rearrangement, Mutation, Comparative Genomic Hybridization, High-Throughput Nucleotide Sequencing, RNA-Binding Proteins, Gene rearrangement, medicine.disease, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Cancer research, Human
Abstract

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

Published
2016

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