Related Experiment Video

Updated: Jul 2, 2025

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

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Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate

Antje Neeb1, Ines Figueiredo1, Denisa Bogdan1

  • 1Institute of Cancer Research, London, United Kingdom.

Molecular Cancer Therapeutics
|February 27, 2024
PubMed

Insights

Targeting BCL-2-associated athanogene-1 (BAG-1) shows promise for castration-resistant prostate cancer (CRPC). Inhibiting BAG-1 with Thio-2 suppressed tumor growth, suggesting new therapeutic avenues for CRPC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Castration-resistant prostate cancer (CRPC) progression is driven by persistent androgen receptor (AR) signaling.
  • The AR N-terminal domain is a challenging target for CRPC therapies.
  • BCL-2-associated athanogene-1 (BAG-1) is highly expressed in CRPC and linked to AR signaling.

Purpose of the Study:

  • To investigate BAG-1 as a therapeutic target in CRPC.
  • To evaluate the efficacy of BAG-1 inhibition in preclinical CRPC models.
  • To explore the role of BAG-1 isoforms in prostate cancer progression.

Main Methods:

  • Analysis of BAG-1 mRNA expression in CRPC.
  • Interrogation of BAG-1's BAG domain properties for drug targeting.
  • BAG-1 isoform mouse knockout studies.
  • Treatment of CRPC cell lines and patient-derived models with Thio-2, a BAG-1 inhibitor.

Main Results:

  • BAG-1 is highly expressed and associated with AR signaling in CRPC.
  • BAG-1 isoforms regulate hormone physiology with potential for limited on-target toxicity.
  • Thio-2 suppressed AR signaling and other key pathways, reducing treatment-resistant prostate cancer growth.
  • Genomic abrogation of BAG-1 could not fully replicate Thio-2's effects, indicating a complex mechanism.

Conclusions:

  • BAG-1 is a druggable target in CRPC.
  • Thio-2 demonstrates therapeutic potential by inhibiting AR signaling and reducing tumor growth.
  • Further investigation of BAG-1 inhibitors with improved properties is warranted for CRPC treatment.
  • Targeting persistent AR signaling remains a critical strategy in CRPC therapy.

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