Validating HER3 as a Therapeutic Target for Advanced Prostate Cancer: from Bench to Bedside
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Embargo End Date
2026-02-04
ICR Authors
Authors
Miranda, S
Document Type
Thesis or Dissertation
Date
2025-08-04
Date Accepted
Abstract
The dysregulation of the ErbB receptor family, particularly HER2 and HER3, has long been implicated in the pathogenesis of prostate cancer. Despite numerous clinical attempts, targeting ErbB receptors has largely been unsuccessful. However, recent advances in targeted therapies, such as antibody-drug conjugates, have revitalised the potential of these receptors as therapeutic targets.This thesis investigated the clinical significance of the ErbB receptor family in advanced prostate cancer and evaluated their potential as drug targets. The data demonstrated that membranous HER3 protein was commonly expressed in lethal prostate cancer, associating with reduced time to castration resistance and worse overall survival. In vitro studies in murine transgenic prostate cancer models, single cell RNAseq of human prostate cancer biopsies and multiplex immunofluorescence assays indicated that the HER3 ligand NRG1 was detectable primarily in tumour-infiltrating myelomonocytic cells. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids (PDX-O), recombinant NRG1 enhanced proliferation, when HER3 expression was present. The anti-HER3 antibody-drug conjugate U3-1402 demonstrated significant antitumour activity in vitro and in vivo in HER3 positive metastatic CRPC patient models. A clinical trial of an anti-HER3 antibody, HMBD-001, is ongoing as a single agent and in combination with an AR antagonist; HER3 biomarker-driven patient selection is being pursued. Trials of anti-HER3 immunoconjugates and radioimmunoconjugates are also ongoing. It is envisioned that these trials will bring ErbB targeting therapies to prostate cancer care.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Cancer Biomarkers