BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations

被引：29

作者：

Markowski, Mark C. ^{[1
]}

De Marzo, Angelo M. ^{[1
,2
,3
]}

Antonarakis, Emmanuel S. ^{[1
,3
]}

机构：

[1] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Oncol, Baltimore, MD USA

[2] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Dept Urol, Brady Urol Inst, Baltimore, MD USA

来源：

EXPERT OPINION ON INVESTIGATIONAL DRUGS | 2017年 / 26卷 / 12期

关键词：

Bromodomain; epigenetics; prostate cancer; drug combinations; BET; BROMODOMAIN PROTEIN BRD4; ANDROGEN-RECEPTOR; INCREASED SURVIVAL; STEM-CELLS; P-TEFB; C-MYC; RESISTANCE; ENZALUTAMIDE; ABIRATERONE; PTEN;

D O I：

10.1080/13543784.2017.1393518

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Introduction: The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR).Areas covered: We speculate that a combination approach using inhibitors of BET proteins (BETi) with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BETi together with other agents in prostate cancer. A literature search using Pubmed was performed for this review.Expert opinion: Use of BETi in the treatment of mCRPC patients may require the addition of a second novel agent.

引用

页码：1391 / 1397

页数：7

共 62 条

[1] The Molecular Taxonomy of Primary Prostate Cancer [J].

Abeshouse, Adam ;

Ahn, Jaeil ;

Akbani, Rehan ;

Ally, Adrian ;

Amin, Samirkumar ;

Andry, Christopher D. ;

Annala, Matti ;

Aprikian, Armen ;

Armenia, Joshua ;

Arora, Arshi ;

Auman, J. Todd ;

Balasundaram, Miruna ;

Balu, Saianand ;

Barbieri, Christopher E. ;

Bauer, Thomas ;

Benz, Christopher C. ;

Bergeron, Alain ;

Beroukhim, Rameen ;

Berrios, Mario ;

Bivol, Adrian ;

Bodenheimer, Tom ;

Boice, Lori ;

Bootwalla, Moiz S. ;

dos Reis, Rodolfo Borges ;

Boutros, Paul C. ;

Bowen, Jay ;

Bowlby, Reanne ;

Boyd, Jeffrey ;

Bradley, Robert K. ;

Breggia, Anne ;

Brimo, Fadi ;

Bristow, Christopher A. ;

Brooks, Denise ;

Broom, Bradley M. ;

Bryce, Alan H. ;

Bubley, Glenn ;

Burks, Eric ;

Butterfield, Yaron S. N. ;

Button, Michael ;

Canes, David ;

Carlotti, Carlos G. ;

Carlsen, Rebecca ;

Carmel, Michel ;

Carroll, Peter R. ;

Carter, Scott L. ;

Cartun, Richard ;

Carver, Brett S. ;

Chan, June M. ;

Chang, Matthew T. ;

Chen, Yu .

CELL, 2015, 163 (04) :1011-1025

[2] BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells [J].

Alghamdi, Saeed ;

Khan, Irfan ;

Beeravolu, Naimisha ;

McKee, Christina ;

Thibodeau, Bryan ;

Wilson, George ;

Chaudhry, G. Rasul .

STEM CELL RESEARCH & THERAPY, 2016, 7

[3] Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study [J].

Amorim, Sandy ;

Stathis, Anastasios ;

Gleeson, Mary ;

Iyengar, Sunil ;

Magarotto, Valeria ;

Leleu, Xavier ;

Morschhauser, Franck ;

Karlin, Lionel ;

Broussais, Florence ;

Rezai, Keyvan ;

Herait, Patrice ;

Kahatt, Carmen ;

Lokiec, Francois ;

Salles, Gilles ;

Facon, Thierry ;

Palumbo, Antonio ;

Cunningham, David ;

Zucca, Emanuele ;

Thieblemont, Catherine .

LANCET HAEMATOLOGY, 2016, 3 (04) :E196-E204

[4] Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer [J].

Annala, Matti ;

Struss, Werner J. ;

Warner, Evan W. ;

Beja, Kevin ;

Vandekerkhove, Gillian ;

Wong, Amanda ;

Khalaf, Daniel ;

Seppala, Irma-Liisa ;

So, Alan ;

Lo, Gregory ;

Aggarwal, Rahul ;

Small, Eric J. ;

Nykter, Matti ;

Gleave, Martin E. ;

Chi, Kim N. ;

Wyatt, Alexander W. .

EUROPEAN UROLOGY, 2017, 72 (01) :34-42

[5]

[Anonymous], N ENGL J MED

[6] Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting [J].

Antonarakis, E. S. ;

Armstrong, A. J. ;

Dehm, S. M. ;

Luo, J. .

PROSTATE CANCER AND PROSTATIC DISEASES, 2016, 19 (03) :231-241

[7] Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration- Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide [J].

Antonarakis, Emmanuel S. ;

Lu, Changxue ;

Luber, Brandon ;

Wang, Hao ;

Chen, Yan ;

Zhu, Yezi ;

Silberstein, John L. ;

Taylor, Maritza N. ;

Maughan, Benjamin L. ;

Denmeade, Samuel R. ;

Pienta, Kenneth J. ;

Paller, Channing J. ;

Carducci, Michael A. ;

Eisenberger, Mario A. ;

Luo, Jun .

JOURNAL OF CLINICAL ONCOLOGY, 2017, 35 (19) :2149-+

[8] Germline DNA Repair Mutations and Response to Hormonal Therapy in Advanced Prostate Cancer [J].

Antonarakis, Emmanuel S. .

EUROPEAN UROLOGY, 2017, 72 (01) :43-44

[9] Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer [J].

Antonarakis, Emmanuel S. ;

Lu, Changxue ;

Luber, Brandon ;

Wang, Hao ;

Chen, Yan ;

Nakazawa, Mary ;

Nadal, Rosa ;

Paller, Channing J. ;

Denmeade, Samuel R. ;

Carducci, Michael A. ;

Eisenberger, Mario A. ;

Luo, Jun .

JAMA ONCOLOGY, 2015, 1 (05) :582-591

[10] AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer [J].

Antonarakis, Emmanuel S. ;

Lu, Changxue ;

Wang, Hao ;

Luber, Brandon ;

Nakazawa, Mary ;

Roeser, Jeffrey C. ;

Chen, Yan ;

Mohammad, Tabrez A. ;

Chen, Yidong ;

Fedor, Helen L. ;

Lotan, Tamara L. ;

Zheng, Qizhi ;

De Marzo, Angelo M. ;

Isaacs, John T. ;

Isaacs, William B. ;

Nadal, Rosa ;

Paller, Channing J. ;

Denmeade, Samuel R. ;

Carducci, Michael A. ;

Eisenberger, Mario A. ;

Luo, Jun .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (11) :1028-1038

← 1 2 3 4 5 6 7 →