Strategies to reverse treatment resistance in castration resistant prostate cancer (CRPC)
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Embargo End Date
2026-01-09
ICR Authors
Authors
Chandran, K
Document Type
Thesis or Dissertation
Date
2025-07-09
Date Accepted
Abstract
Prostate cancer (PC) growth and progression is usually dependent on androgens and androgen receptor (AR) signalling. Much research to date on metastatic castrate resistant prostate cancer (mCRPC) has focused on mechanisms of deregulated AR signalling. AR targeted therapies increase overall survival from aggressive PC, however, resistance is usually inevitable. PC cells are believed to be dependent on the tumour microenvironment (TME) to support tumour progression. Myelomonocytic cells, including a cell type described as myeloid-derived suppressor cells (MDSCs), have emerged as important players in prostate cancer biology, arguably supporting tumourigenesis. MDSCs have been reported to fuel AR signalling and drive castration resistance by releasing interleukin-23 (IL-23) and neuregulin-1 (NRG-1) in a paracrine fashion; IL-23 is implicated in may act directly on tumour cells to promote their growth. Myelomonocytic cells also generate the HER3 ligand NRG1; preclinical findings indicate that HER3 activation by NRG-1 generated by myelomonocytic cells is a therapeutic target in advanced PC. The gastrointestinal (GI) microbiota are also implicated in carcinogenesis, perhaps impacting myelomonocytic inflammation and PC progression. In preclinical mouse models, gut microbial composition is linked to the development of endocrine resistance. Nevertheless, the mechanisms by which microbiota impact prostate carcinogenesis and PC growth remain underexplored, although it has been reported that GI microbiota can synthesise androgenic steroids and carcinogens. This MD (Res) thesis brings together translational and clinical research to systematically dissect how MDSCs and GI microbiota contribute to PC growth, mechanisms of resistance, and how it can be modulated to prevent and treat PC, validating and qualifying a multiplex biomarker assay that can then be utilized in therapeutic and prevention studies. These findings will be of direct therapeutic relevance since mechanistic elucidation of the interaction between MDSCs, host microbiota and prostate tumours will facilitate the design of interventions to improve outcome from PC.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Adult DDU ICR & RM