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Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer

Harris, Anna E.; Metzler, Veronika M.; Lothion-Roy, Jennifer; Varun, Dhruvika; Woodcock, Corinne L.; Haigh, Daisy B.; Endeley, Chantelle; Haque, Maria; Toss, Michael S.; Alsaleem, Mansour; Persson, Jenny L.; Gudas, Lorraine J.; Rakha, Emad; Robinson, Brian D.; Khani, Francesca; Martin, Laura M.; Moyer, Jenna E.; Brownlie, Juliette; Madhusudan, Srinivasan; Allegrucci, Cinzia; James, Victoria H.; Rutland, Catrin S.; Fray, Rupert G.; Ntekim, Atara; de Brot, Simone; Mongan, Nigel P.; Jeyapalan, Jennie N.

Authors

Anna E. Harris

Veronika M. Metzler

Jennifer Lothion-Roy

Dhruvika Varun

Daisy B. Haigh

Chantelle Endeley

Maria Haque

Michael S. Toss

Mansour Alsaleem

Jenny L. Persson

Lorraine J. Gudas

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Brian D. Robinson

Francesca Khani

Laura M. Martin

Jenna E. Moyer

Juliette Brownlie

RUPERT FRAY rupert.fray@nottingham.ac.uk
Professor of Epitranscriptomics

Atara Ntekim

Simone de Brot



Abstract

Androgen deprivation therapies (ADTs) are important treatments which inhibit androgen-induced prostate cancer (PCa) progression by either preventing androgen biosynthesis (e.g. abiraterone) or by antagonizing androgen receptor (AR) function (e.g. bicalutamide, enzalutamide, darolutamide). A major limitation of current ADTs is they often remain effective for limited durations after which patients commonly progress to a lethal and incurable form of PCa, called castration-resistant prostate cancer (CRPC) where the AR continues to orchestrate pro-oncogenic signalling. Indeed, the increasing numbers of ADT-related treatment-emergent neuroendocrine-like prostate cancers (NePC), which lack AR and are thus insensitive to ADT, represents a major therapeutic challenge. There is therefore an urgent need to better understand the mechanisms of AR action in hormone dependent disease and the progression to CRPC, to enable the development of new approaches to prevent, reverse or delay ADT-resistance. Interestingly the AR regulates distinct transcriptional networks in hormone dependent and CRPC, and this appears to be related to the aberrant function of key AR-epigenetic coregulator enzymes including the lysine demethylase 1 (LSD1/KDM1A). In this review we summarize the current best status of anti-androgen clinical trials, the potential for novel combination therapies and we explore recent advances in the development of novel epigenetic targeted therapies that may be relevant to prevent or reverse disease progression in patients with advanced CRPC.

Citation

Harris, A. E., Metzler, V. M., Lothion-Roy, J., Varun, D., Woodcock, C. L., Haigh, D. B., …Jeyapalan, J. N. (2022). Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer. Frontiers in Endocrinology, 13, Article 1006101. https://doi.org/10.3389/fendo.2022.1006101

Journal Article Type Article
Acceptance Date Sep 16, 2022
Online Publication Date Oct 3, 2022
Publication Date Oct 3, 2022
Deposit Date Oct 5, 2022
Publicly Available Date Oct 5, 2022
Journal Frontiers in Endocrinology
Electronic ISSN 1664-2392
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 13
Article Number 1006101
DOI https://doi.org/10.3389/fendo.2022.1006101
Keywords Endocrinology, Therapy, anti-androgen, castration resistant prostate cancer, PARP inhibitors, epigenetic targeted treatment
Public URL https://nottingham-repository.worktribe.com/output/12029672
Publisher URL https://www.frontiersin.org/articles/10.3389/fendo.2022.1006101/full

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