Thio-2 inhibits key signaling pathways required for the development and progression of castration resistant prostate cancer.


Journal

Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535

Informations de publication

Date de publication:
27 Feb 2024
Historique:
accepted: 22 02 2024
received: 08 06 2023
revised: 26 09 2023
medline: 27 2 2024
pubmed: 27 2 2024
entrez: 27 2 2024
Statut: aheadofprint

Résumé

Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BAG-1 mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited 'on-target' toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment resistant prostate cancer cell lines and patient derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation since the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2 mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.

Identifiants

pubmed: 38412481
pii: 734951
doi: 10.1158/1535-7163.MCT-23-0354
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Auteurs

Antje Neeb (A)

Institute of Cancer Research, Surrey, United Kingdom.

Ines Figueiredo (I)

Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Denisa Bogdan (D)

Institute of Cancer Research, London, United Kingdom.

Laura Cato (L)

Dana-Farber Cancer Institute, Boston, MA, United States.

Jutta Stober (J)

Karlsruhe Institute of Technology, Germany.

Juan M Jiménez-Vacas (JM)

Institute of Cancer Research, London, United Kingdom.

Victor Gourain (V)

Nantes University, Nantes, France.

Irene I Lee (II)

AbbVie (United States), North Chicago, IL, United States.

Rebecca Seeger (R)

Karlsruhe Institute of Technology, Germany.

Claudia Muhle-Goll (C)

Karlsruhe Institute of Technology, Germany.

Bora Gurel (B)

Institute of Cancer Research, London, United Kingdom.

Jonathan Welti (J)

Institute of Cancer Research, London, United Kingdom.

Daniel Nava Rodrigues (D)

Institute of Cancer Research, London, United Kingdom.

Jan Rekowski (J)

Institute of Cancer Research, London, United Kingdom.

Xintao Qiu (X)

Dana-Farber Cancer Institute, Boston, MA, United States.

Yija Jiang (Y)

Dana-Farber Cancer Institute, United States.

Patrizio Di Micco (P)

Institute of Cancer Research, London, United Kingdom.

Borja Mateos (B)

Institute of Biomedical Research of Barcelona, Spain.

Stasė Bielskutė (S)

Institute for Research in Biomedicine, Spain.

Ruth Riisnaes (R)

Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Ana Ferreira (A)

Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Susana Miranda (S)

Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Mateus Crespo (M)

Institute of Cancer Research, Sutton, United Kingdom.

Lorenzo Buroni (L)

Institute of Cancer Research, London, United Kingdom.

Jian Ning (J)

Institute of Cancer Research, London, United Kingdom.

Suzanne Carreira (S)

Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Stefan Bräse (S)

KIT Campus South, Institute of Organic Chemistry, Karlsruhe, Germany.

Nicole Jung (N)

Karlsruhe Institute of Technology, Karlsruhe, Germany.

Simone Gräßle (S)

Karlsruhe Institute of Technology (KIT), Karlsruhe, Eggenstein-Leopoldshafen, Germany.

Amanda Swain (A)

Institute of Cancer Research, London, United Kingdom.

Xavier Salvatella (X)

Institute for Research in Biomedicine, Barcelona, Spain.

Stephen R Plymate (SR)

University of Washington, Seattle, Washington, United States.

Bissan Al-Lazikani (B)

Institute of Cancer Research, Houston, TX, United States.

Henry W Long (HW)

Dana-Farber Cancer Institute, Boston, MA, United States.

Wei Yuan (W)

Institute of Cancer Research, Sutton, United Kingdom.

Myles Brown (M)

Dana-Farber Cancer Institute, Boston, MA, United States.

Andrew C B Cato (ACB)

Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.

Johann S de Bono (JS)

Institute of Cancer Research, London, United Kingdom.

Adam Sharp (A)

Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Classifications MeSH