Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer

Wyce, Anastasia; Degenhardt, Yan; Bai, Yuchen; Le, BaoChau; Korenchuk, Susan; Crouthamel, Ming Chih; McHugh, Charles F.; Vessella, Robert L.; Creasy, Caretha L.; Tummino, Peter J.; Barbash, Olena

doi:10.18632/oncotarget.1572

Cited by 158 publications

(129 citation statements)

References 30 publications

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“…Cofactor inhibitors would have the hypothesized advantage that as they are "downstream" of AR, resistance cannot easily be brought about by upregulation of AR or its ligand, making the case for cofactor inhibitor use up-front in combination with traditional antiandrogens to enhance efficacy and block potential resistance mechanisms. Advances in technologies to interrogate chromatin have resulted in the identification of a number of essential AR coactivators and their proposal as potential drug targets (30,(42)(43)(44)(45). Historically, such cofactors and epigenetic regulators have proved notoriously difficult targets for the design of small-molecule inhibitors, hindering progress in this area.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Jin¹,

Garcia²,

Chan³

et al. 2017

Cancer Research

114

100

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Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castrationresistant prostate cancer. Cancer Res; 77(20); 5564-75. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Jin¹,

Garcia²,

Chan³

et al. 2017

Cancer Research

114

100

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“…Preclinical evidence of I-BET762 antitumour activity in myeloma, acute leukaemia and solid cancers, including the NUT midline carcinoma was demonstrated in later studies. Owing to its favourable pharmacological profile I-BET762 is one of the several BET protein inhibitors currently tested in early phase clinical trials [Mirguet et al 2013;Wyce et al 2013a;Zhao et al 2013b;Asangani et al 2014;Chaidos et al 2014].…”

Section: The Development Of the Bet Proteins Inhibitorsmentioning

confidence: 99%

Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence

Chaidos

Caputo

Karadimitris

2015

Therapeutic Advances in Hematology

142

103

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Post-translational modifications of the nucleosomal histone proteins orchestrate chromatin organization and gene expression in normal and cancer cells. Among them, the acetylation of N-terminal histone tails represents the fundamental epigenetic mark of open structure chromatin and active gene transcription. The bromodomain and extra-terminal (BET) proteins are epigenetic readers which utilize tandem bromodomains (BRD) modules to recognize and dock themselves on the acetylated lysine tails. The BET proteins act as scaffolds for the recruitment of transcription factors and chromatin organizers required in transcription initiation and elongation. The recent discovery of small molecules capable of blocking their lysine-binding pocket is the first paradigm of successful pharmacological inhibition of epigenetic readers. JQ1 is a prototype benzodiazepine molecule and a specific BET inhibitor with antineoplastic activity both in solid tumours and haematological malignancies. The quinolone I-BET151 and the suitable for clinical development I-BET762 benzodiazepine were introduced in parallel with JQ1 and have also shown potent antitumour activity in preclinical studies. I-BET762 is currently being tested in early phase clinical trials, along with a rapidly growing list of other BET inhibitors. Unlike older epigenetic therapies, the study of BET inhibitors has offered substantial, context-specific, mechanistic insights of their antitumour activity, which will facilitate optimal therapeutic targeting in future. Here, we review the development of this novel class of epigenetic drugs, the biology of BET protein inhibition, the emerging evidence from preclinical work and early phase clinical studies and we discuss their potential role in the treatment of haematological malignancies.

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“…Using a novel in vivo delivery system, Civenni et al (2013) demonstrated that the systemic delivery of Myc-targeted siRNA to mice bearing PC-3 CRPC xenografts reduced the CSC population and suppressed tumor growth and metastasis. Although MYC inhibitor design has been difficult because of the absence of a clear ligand binding domain, BET inhibitors have been shown to reduce MYC expression in PCa models (Wyce et al 2013) and have demonstrated astounding therapeutic efficacy in blocking CRPC tumor growth (Asangani et al 2014). Alternatively, targeting EZH2 has gained traction within the sphere of CSC-directed therapy.…”

Section: Tumor Cell Plasticity: Overlap In Aggressive Cell Phenotypesmentioning

confidence: 99%

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

Bishop¹,

Davies

Ketola

et al. 2015

Endocrine-Related Cancer

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Prostate cancer (PCa) has become the most common form of cancer in men in the developed world, and it ranks second in cancer-related deaths. Men that succumb to PCa have a disease that is resistant to hormonal therapies that suppress androgen receptor (AR) signaling, which plays a central role in tumor development and progression. Although AR continues to be a clinically relevant therapeutic target in PCa, selection pressures imposed by androgendeprivation therapies promote the emergence of heterogeneous cell populations within tumors that dictate the severity of disease. This cellular plasticity, which is induced by androgen deprivation, is the focus of this review. More specifically, we address the emergence of cancer stem-like cells, epithelial-mesenchymal or myeloid plasticity, and neuroendocrine transdifferentiation as well as evidence that demonstrates how each is regulated by the AR. Importantly, because all of these cell phenotypes are associated with aggressive PCa, we examine novel therapeutic approaches for targeting therapy-induced cellular plasticity as a way of preventing PCa progression.

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Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer

Cited by 158 publications

References 30 publications

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

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