All Publications

PK/PD MODELING OF THE FIRST-IN-CLASS, POTENT AND SELECTIVE COVALENT CDK7 INHIBITOR, SY-1365, PROVIDES MECHANISTIC BASIS FOR INTERMITTENT DOSING REGIMENS IN PRECLINICAL EFFICACY MODELS OF HEMATOLOGICAL AND SOLID TUMORS

Nigel J. Waters, Shanhu Hu, Brett Matzuka, Graeme Hodgson, Yixuan Ren, Yoon Choi, Kevin Dykstra, Christopher Roberts, Kevin Sprott, Emmanuelle di Tomaso, Christian C. Fritz
AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference
Abstract Number: B171
2017

CHARACTERIZING THE EPIGENETIC LANDSCAPE IDENTIFIES PUTATIVE THERAPEUTIC TARGETS IN THE PANCREATIC CANCER CHIMERA

Divya Sood MD, Kathryn Austgen PhD, Chris Fiore PhD, David Orlando PhD, Brian Johnston MS, Sofija Miljovska MS, Cindy Collins MS, Randall French PhD, Yu Shi PhD, Tony Hunter PhD, Tracey Lodie PhD, Andrew Lowy MD
American College Surgeons
2017

SUPPRESSION OF ADAPTIVE RESPONSES TO TARGETED CANCER THERAPY BY TRANSCRIPTIONAL REPRESSION

Maria Rusan, Kapsok Li, Yvonne Li, Camilla L. Christensen, Brian J. Abraham, Nicholas Kwiatkowski, Kevin A. Buczkowski, Bruno Bockorny, Ting Chen, Shuai Li, Kevin Rhee, Haikuo Zhang, Wankun Chen, Hideki Terai, Tiffany Tavares, Alan L. Leggett, Tianxia Li, Yichen Wang, Tinghu Zhang, Tae-Jung Kim, Sook-Hee Hong, Neermala Poudel-Neupane, Michael Silkes, Tenny Mudianto, Li Tan, Takeshi Shimamura, Matthew Meyerson, Adam J. Bass, Hideo Watanabe, Nathanael S. Gray, Richard A. Young, Kwok-Kin Wong and Peter S. Hammerman
Cancer Discovery DOI: 10.1158/2159-8290.CD-17-0461
October 20, 2017

RARA PATHWAY ACTIVATION BIOMARKERS IN STUDY SY-1425-201 DEFINE A NEW SUBSET OF AML AND MDS PATIENTS AND CORRELATE WITH MYELOID DIFFERENTIATION FOLLOWING EX VIVO SY-1425 TREATMENT

Carlos E. Vigil, Joseph Jurcic, Azra Raza, Rachel Cook, Dale Bixby, Mikkael Sekeres, David Rizzieri, Eytan Stein, Robert L. Redner, David Steensma, Gail Roboz, Michael Savona, Michael McKeown, Chris Fiore, Angela Volkert, Curran Murphy, Kristin Stephens, David A. Roth, Emmanuelle di Tomaso, Jorge Cortes.
ESH Conference on AML
Abstract Number: 8882
2017

TARGETING THE NONCODING GENOME: SUPERENHANCERS MEET THEIR KRYPTONITE

Eric Wang and Ioannis Aifantis
Cancer Discovery (7) (10) 1065-1066; DOI: 10.1158/2159-8290.CD-17-0860
October 1, 2017

PHARMACODYNAMIC AND PHARMACOKINETIC EVALUATION OF SY-1425 (TAMIBAROTENE) IN BIOMARKER-SELECTED ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS) PATIENTS

Dale Bixby, Carlos E. Vigil, Joseph Jurcic, Rachel Cook, Mikkael Sekeres, David Rizzieri, Jorge Cortes, Robert Redner, David Steensma, Gail Roboz, Tamara Moyo, Michael R McKeown, Nigel J. Waters, Kristin Stephens, Emmanuelle di Tomaso, David A. Roth, Eytan Stein
ESMO Congress
Abstract Number: 1032P
2017

A PHASE 1 STUDY OF SY-1365, A SELECTIVE CDK7 INHIBITOR, IN ADULT PATIENTS WITH ADVANCED SOLID TUMORS

Anthony Tolcher, Khanh T. Do, Emmanuelle di Tomaso, Nigel J. Waters, Kristin Stephens, David A. Roth, Geoffrey Shapiro
ESMO Congress
Abstract Number: 425TiP
2017

A BIOMARKER-DIRECTED PHASE 2 STUDY OF SY-1425, A SELECTIVE RETINOIC ACID RECEPTOR ALPHA AGONIST, IN ADULT PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS)

Rachel Cook, Eytan Stein, David Steensma, Mikkael Sekeres, Dale Bixby, David Rizzieri, Joseph Jurcic, Carlos E. Vigil, Robert Redner, Gail Roboz, Michael Savona, Michael R. McKeown, Kristin Stephens, David A. Roth, Jorge Cortes
ASCO Annual Meeting
Abstract Number: TPS7071
2017

SUPER-ENHANCER ANALYSIS DEFINES NOVEL EPIGENOMIC SUBTYPES OF NON-APL AML INCLUDING AN RARΑ DEPENDENCY TARGETABLE BY SY-1425, A POTENT AND SELECTIVE RARΑ AGONIST

McKeown M. Et al.
Cancer Discovery
doi: 10.1158/2159-8290.CD-17-0399
2017

MECHANISTICALLY INFORMED COMBINATIONS OF SY-1425, A POTENT AND SELECTIVE RARΑ AGONIST, WITH HYPOMETHYLATING OR ANTI-CD38 TARGETED AGENTS IN AML AND MDS

Michael R McKeown, Kathryn Austgen, Chris Fiore, Emily Lee, Darren Smith, Christian Fritz, Tracey Lodie, Emmanuelle di Tomaso, Eric Olson
EHA 22nd Congress
Abstract Number: P188
2017

SY-1425, A POTENT AND SELECTIVE RARΑ AGONIST, REPROGRAMS AML CELLS FOR DIFFERENTIATION ALONG DISTINCT LINEAGES, UNCOVERING PD MARKERS FOR CLINICAL STUDIES

Michael R McKeown, Chris Fiore, Kathryn Austgen, Emily Lee, Darren Smith, Mei Wei Chen, Matthew L Eaton, Angela Volkert, Curran Murphy, Kristin Stephens, Christian Fritz, Tracey Lodie, Emmanuelle di Tomaso and Eric Olson
EHA 22nd Congress
Abstract Number: E884
2017

THE EPIGENETIC LANDSCAPE OF T CELL SUBSETS IN SLE IDENTIFIES KNOWN AND POTENTIAL NOVEL DRIVERS OF THE AUTOIMMUNE RESPONSE

Jozsef Karman, Brian Johnston, Sofija Miljovska, David Orlando, Eric Olson and Tracey Lodie
Federation of Clinical Immunology Societies (FOCIS) 17th Annual Meeting: Late-breaking Oral Presentation
Abstract Number: 319030
June 16, 2017

SY-1425 (TAMIBAROTENE), A POTENT SELECTIVE RARA AGONIST, INDUCES CHANGES IN THE TRANSCRIPTIONAL REGULATORY CIRCUIT OF AML CELLS LEADING TO DIFFERENTIATION

Chris Fiore, Michael R. Mckeown, Emily Lee, Matthew L. Eaton, Darren Smith, Kathryn Austgen, Mei Wei Chen, Matthew Guenther, M. Ryan Corces, Ravindra Majeti, Eric Olson And Christian Fritz
AACR Annual Hematologic Malignancies Meeting
Poster Section: 6
2017

EPIGENOMIC ANALYSIS OF PRIMARY BREAST CANCER TUMORS REVEALS NOVEL TUMOR CELL VULNERABILITIES AND THERAPEUTIC TARGETS

Matthew G. Guenther, Mei Wei Chen, Christina Kolodzy, Michael McKeown, Emily Lee, Cindy Collins, Matthew Eaton, David Orlando, Emmanuelle di Tomaso,
Christian C. Fritz, Eric R. Olson.
IMPAKT Breast Cancer Conference
Abstract Number: 47P
2017

SY-1425 (TAMIBAROTENE), A SELECTIVE RARA AGONIST, SHOWS SYNERGISTIC ANTI-TUMOR ACTIVITY WITH HYPOMETHYLATING AGENTS IN A BIOMARKER SELECTED SUBSET OF AML

Michael R. McKeown, Emily Lee, Chris Fiore, Matthew L. Eaton, Christian Fritz and Eric Olson
AACR Annual Meeting
Poster Section: 3
Abstract Number: 3085
2017

SY-1425, A SELECTIVE RARA AGONIST, INDUCES HIGH LEVELS OF CD38 EXPRESSION IN RARA-HIGH AML TUMORS CREATING A SUSCEPTIBILITY TO ANTI-CD38 THERAPEUTIC ANTIBODY TREATMENT

Kathryn Austgen, Michael R. McKeown, Darren Smith, Emily Lee, Chris Fiore, Matthew L. Eaton, Christian Fritz, Tracey Lodie and Eric Olson
AACR Annual Meeting
Poster Section: 26
Abstract Number: 2644
2017

AML PATIENT CLUSTERING BY SUPER-ENHANCERS REVEALS AN RARA ASSOCIATED TRANSCRIPTION FACTOR SIGNALLING PARTNER

Michael R. McKeown, Matthew L. Eaton, Chris Fiore, Emily Lee, Kathryn Austgen, Darren Smith, Ryan Corces, Ravindra Majeti and Christian Fritz
AACR Annual Meeting
Poster Section: 20
Abstract Number: 1511
2017

SY-1365, A POTENT AND SELECTIVE CDK7 INHIBITOR, EXHBITS PROMISING ANTI-TUMOR ACTIVITY IN MULTIPLE PRECLNICAL MODELS OF AGGRESSIVE SOLID TUMORS

Shanhu Hu, Nan Ke, Yixuan Ren, Sofija Miljovska, Nisha Rajagopal, Michael McKeown, David Orlando, Kevin Sprott, Yoon Choi, Eric Olson and Christian Fritz
AACR Annual Meeting
Poster Section: 4
Abstract Number: 1151
2017

TARGETING THE TRANSCRIPTIONAL KINASES CDK12 AND CDK13 IN BREAST AND OVARIAN CANCER

Michael Bradley, Kristin Hamman, David Orlando, Shanhu Hu, Jason Marineau, Nan Ke, Sherry Ren, Yoon Choi, Christopher Roberts, Christian Fritz and Eric Olson
AACR Annual Meeting
Poster Section: 4
Abstract Number: 1143
2017

SUPER-ENHANCER LANDSCAPES REVEAL NOVEL EPIGENOMIC PATIENT SUBTYPES AND DRUGGABLE DEPENDENCIES IN HUMAN AML

Matthew L. Eaton, M. Ryan Corces, Michael R. McKeown, Chris Fiore, Jeremy T. Lopez, Katarzyna Piotrowska, Emily Lee, Mei Wei Chen, Darren Smith, Steven M. Chan, Julie L. Koening, Sarah K. Knutson, Kathryn Austgen, Matt G. Guenther, Dave Orlando, Jakob Loven, Christian Fritz and Ravindra Majeti.
CSHL Systems Biology Meeting
2017

TRANSCRIPTIONAL ADDICTION IN CANCER

James E. Bradner, Denes Hnisz, and Richard A. Young.
Cell
doi: http://dx.doi.org/10.1016/j.cell.2016.12.013
February 9, 2017

A NOVEL SUBGROUP OF ESTROGEN RECEPTOR POSITIVE BREAST CANCER MAY BENEFIT FROM SUPER-ENHANCER GUIDED PATIENT SELECTION FOR RETINOIC ACID RECEPTOR ALPHA AGONIST TREATMENT

Michael R. McKeown, Chris Fiore, Emily Lee, Matthew L. Eaton, Dave Orlando, Matt G. Guenther, Cindy Collins, Mei Wei Chen, Christian Fritz and Emmanuelle di Tomaso
SABCS Annual Meeting
Session: Treatment: Novel Targets and Targeted Agents
Program Number: P6-11-18
2016

SY-1425 (TAMIBAROTENE) INDUCES PROFOUND TRANSCRIPTIONAL CHANGES IN AML TUMORS WITH HIGH RETINOIC ACID RECEPTOR ALPHA

Chris Fiore, Michael McKeown, Emily Lee, Matthew L. Eaton, and Christian Fritz
ASH Annual Meeting
Poster Section: 128
Abstract Number: 1523
2016

CLINICAL PHARMACODYNAMIC MARKERS AND COMBINATIONS WITH SY-1425 (TAMIBAROTENE) IN A GENOMICALLY-DEFINE SUBSET OF NON-APL AML

Michael R. McKeown, Chris Fiore, Emily Lee, Matthew L. Eaton, Kathryn Austgen, Darren Smith and Christian Fritz
ASH Annual Meeting
Poster Section: 128
Abstract Number: 2898
2016

COVALENT TARGETING OF REMOTE CYCTEINE RESIDUES TO DEVELOP CDK12 AND CDK13 INHIBITORS

Tinghu Zhang, Nicholas Kwiatkowski, Calla M Olson, Sarah E. Dixon-Clarke, Brian J. Abraham, Ann K. Greifenberg, Scott B. Fiacarro, Jonathan M. Elkins, Yanke Liang, Nancy M Hannett, Theresa Manz, Mingfeng Hao, Bartlomiej Bartkowiak, Arno L. Greenlead, Jarrod A Marto, Matthias Geyer, Alex N. Bullock, Richard A. Young, and Nathanael S. Gray.
Nature Chemical Biology
doi: 10,1038/NCHEMBIO.2166
August 29, 2016

SUPER-ENHANCER ANALYSIS DEFINES NOVEL AML AND MDS SUB-TYPES

Michael R. McKeown, Emily Lee, Chris Fiore, Matthew L. Eaton, Jeremy Lopez, Ryan Corces-Zimmerman, Ravindra Majeti, Kristin Stephens, Christian Fritz, and Eric Olson
EHA 21st Congress
Oral Presentation: Hall A3
Abstract Number: s807
June 12, 2016

FIRST-IN-CLASS CDK7 INHIBITOR, INDUCES ROBUST APOPTOSIS IN ACUTE MYELOID LEUKEMIA AND DEMONSTRATES DURABLE IN VIVO EFFICACY

Yoon Jong Choi, Shanhu Hu, Nan Ke, Yixuan Ren, Jeremy Lopez, Sofija Miljovska, David Orlando, Darby Schmidt, Michael Bradley, Kevin Sprott, Christian Fritz and Eric Olson
EHA 21st Congress
Poster Section: Biology 3
Abstract Number: P558
2016

SY-1425 IN GENOMICALLY DEFINED SUBSET OF AML AND MDS PATIENTS

Michael R. McKeown, Emily Lee, Chris Fiore, Matthew L. Eaton, Jeremy Lopez, Ryan Corces-Zimmerman, Ravindra Majeti, Christian Fritz, and Eric Olson
AACR Annual Meeting
Poster Section: 14
Abstract Number: 1187
2016

CDK7 INHIBITION AS A NOVEL TREATMENT STRATEGY FOR ACUTE LEUKEMIAS

Shanhu Hu, Nan Ke, Yixuan Ren, Jeremy Lopez, Sofija Miljovska, David Orlando, Darby Schmidt, Michael Bradley, Kevin Sprott, Eric Olson, Christian C. Fritz, and Yoon Jong Choi
AACR Annual Meeting
Poster Section: 20
Abstract Number: 4820
2016

ACTIVATION OF PROTO-ONCOGENES BY DISRUPTION OF CHROMOSOME NEIGHBORHOODS

Hnisz D. et al.
Science
doi: 10.1126/science.aad9024
2016

TARGETING TRANSCRIPTIONAL DEPENDENCY IN ACUTE MYELOID LEUKEMIA (AML) WITH A COVALENT INHIBITOR OF TRANSCRIPTIONAL KINASE CDK7

Yixuan Ren, Victoria Brown, Shanhu Hu, Jeremy Lopez, Sofija Miljovska, Darby Schmidt, Michael Bradley, Kevin Sprott, Eric Olson, Christian C. Fritz and, Yoon Jong Choi
ASH Annual Meeting: Session: 616, Poster I
2015

NO DRIVER BEHIND THE WHEEL? TARGETING TRANSCRIPTION IN CANCER

Hector L. Franco, Lee Kraus
Cell
doi:10.1016/j.cell.2015.09.013
2015

CDK7-DEPENDENT TRANSCRIPTIONAL ADDICTION IN TRIPLE-NEGATIVE BREAST CANCER

Yuboa Wang, Tinghu Zhang, Nicholas Kwitowski, Brian J. Abraham, Tong Ihn Lee, Shaozhen Xie, Haluk Yuzugulu, Thanh Von, Heyuan Li, Ziao Lin, Daniel G. Stover, Elgene Lim, Zhiagang C. Wang, J.Dirk Iglehart, Richard A. Young, Nathanael S. Gray, Jean J. Zhao
Cell
doi:10.1016/j.cell.2015.08.063
2015

TARGETING TRANSCRIPTION FACTORS IN CANCER

Anand S. Bhagwat, Christopher R. Vakoc.
Trends in Cancer
doi:10.1016/j.trecan.2015.07.001
2015

SUPER-ENHANCER LANDSCAPES SPECIFY MOLECULAR SUBTYPES AND NOVEL TARGETS IN ACUTE MYELOID LEUKEMIA

Matthew Eaton, Ryan Corces-Zimmerman, Jeremy Lopez, Christian Fritz, Eric Olson, Ravindra Majeti, Jakob Loven.
AACR Annual Meeting: 12.2212.23
2015

SUPER-ENHANCERS DEFINE BREAST CANCER SUBCLASSES AND IDENTIFY NOVEL TUMOR CELL VULNERABILITIES

Cindy Collins, Mei Wei Chen, Matthew Eaton, David Orlando, Michael McKeown, Christian Fritz, Eric Olson, Matthew Guenther.
AACR Annual Meeting: 4.3837.20
2015

CONVERGENCE OF DEVELOPMENTAL AND ONCOGENIC SIGNALING PATHWAYS AT TRANSCRIPTIONAL SUPER-ENHANCERS

Denes Hnisz, Jurian Schuijers, Charles Y. Lin, Abraham S. Weintraub, Brian J. Abraham, Tong Ihn Lee, James E. Bradner, Richard A. Young.
Molecular Cell
doi: 10.1016/j.molcel.2015.02.014
2015

TARGETING TRANSCRIPTIONAL ADDICTIONS IN SMALL CELL LUNG CANCER WITH A COVALENT CDK7 INHIBITOR

Camilla L. Christensen, Nicholas Kwiatkowski, Brian J. Abraham, Julian Carretero, Fatima Al-Shahrour, Tinghu Zhang, Edmond Chipumuro, Grit S. Herter-Sprie, Esra A. Akbay, Abigail Altabef, Jianming Zhang, Takeshi Shimamura, Marzia Capelletti, Jakob B. Reibel, Jillian D. Cavanaugh, Peng Gao, Yan Liu, Signe R. Michaelsen, Hans S. Poulsen, Amir R. Aref, David A. Barbie, James E. Bradner, Rani E. George, Nathanael S. Gray, Richard A. Young, Kwok-Kin Wong.
Cancer Cell
doi: 10.1016/j.cell.2014.10.019
2014

QUANTITATIVE CHIP-SEQ NORMALIZATION REVEALS GLOBAL MODULATION OF THE EPIGENOME

David A. Orlando, Mei Wei Chen, Victoria E. Brown, Snehakumari Solanki, Yoon J. Choi, Eric R. Olson,
Christian C. Fritz, James E. Bradner, and Matthew G. Guenther
Cell Reports, Volume 9, Issue 3, 1163 - 1170
2014

GENOME-WIDE LOCALIZATION OF SMALL MOLECULES

Anders, L., Guenther, M.G., Qi,J., Fan, Z.P., Marineau, J.J., Rahl, P.B., Loven, J, Sigova, A.A., Smith, W.B., Lee, T.I., Bradner, J.E., and Young, R.A.
Nature Biotechnology
doi:10.1038/nbt.2776
2013

DISCOVERY AND CHARACTERIZATION OF SUPER-ENHANCER-ASSOCIATED DEPENDENCIES IN DIFFUSE LARGE B CELL LYMPHOMA

Chapuy,B., McKeown, M.R., Lin, C.Y., Monti, S., Roemer, M.G.M., Qi,J., Rahl, P.B., Sun, H.H., Yeda, K.T., Doench, J.G., Reichert,E., Kung, A.L., Rodig,S.J., Young,R.A., Shipp, M.A., and Bradner, J.E.
Cancer Cell 24:777-790
2013

RICHARD YOUNG INVITED NIH SEMINAR: SUPER-ENHANCERS CONTROL CELL IDENTITY AND DISEASE DRIVERS

2013

SUPER-ENHANCERS IN THE CONTROL OF CELL IDENTITY AND DISEASE

Hnisz,D., Abraham, B.J., Lee, T.I., Lau, A., Saint-Andre,V., Sigova, A.A., Hoke, H.A., and Young, R.A.
Cell 155: 1-14
2013

SELECTIVE INHIBITION OF TUMOR ONCOGENES BY DISRUPTION OF SUPER-ENHANCERS

Lovén, J., Hoke, H.A., Lin, C.Y., Lau, A., Orlando, D.A., Vakoc, C.R., Bradner, J.E., Lee, T.I., and Young, R.A.
Cell 153: 320-334
2013

MASTER TRANSCRIPTION FACTORS AND MEDIATOR ESTABLISH SUPER-ENHANCERS AT KEY CELL IDENTITY GENES

Whyte, W.A., Orlando, D.A., Hsnisz, D., Abraham, B.J., Lin, C.Y., Kagey, M.H., Rahl, P.B., Lee, T.I., and Young, R.A.
Cell 153: 307-319
2013

TRANSCRIPTIONAL REGULATION AND ITS MISREGULATION IN DISEASE

Lee,T.I., and Young, R.A.
Cell 152: 1237-1251
2013

REVISITING GLOBAL GENE EXPRESSION ANALYSIS

Lovén, J., Orlando, D.A., Sigova, A.A., Lin, C.Y., Rahl, P.B., Burge, C.B., Levens, D.L., Lee, T.I., and Young, R.A.
Cell 151: 476-482
2012

TRANSCRIPTIONAL AMPLIFICATION IN TUMOR CELLS WITH ELEVATED C-MYC

Lin, C.Y., Lovén, J., Rahl, P.B., Paranal, R.M., Burge, C.B., Bradner, J.E., Lee, T.I., and Young, R.A.
Cell 151: 56-67
2012

CONTROL OF THE EMBRYONIC STEM CELL STATE

Young, R.A.
Cell 144: 940-954
2011

C-MYC REGULATES TRANSCRIPTIONAL PAUSE RELEASE

Rahl, P.B., Lin, C.Y., Seila, A.C., Flynn, R.A., McCuine, S., Burge, C.B., Sharp, P.A., and Young, R.A.
Cell 141: 432-445
2010