Elucidating Taxane treatment resistance in lethal prostate cancer
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Date
2024-06-17ICR Author
Author
De Bono J
Weigl, F
De Bono, J
Type
Thesis or Dissertation
Metadata
Show full item recordAbstract
Despite diagnostic and therapeutic advances, prostate cancer remains the most commonly diagnosed
cancer in men, with over 1.2 million new cases worldwide and 20% of cancer-related deaths in men.
While initial androgen deprivation therapy (ADT) leads to remission, this treatment invariably fails, and
the cancer progresses to advanced castration resistant PCa (CRPC) and metastases. Taxane
chemotherapy is an approved treatment for CRPC and disrupts tubulin polymerization dynamics,
mitosis, and DNA integrity, driving tumour cells to cell death. Treatment with Taxanes improves survival
and quality of life but many CRPC patients either do not respond and benefit from treatment or
eventually develop Taxane resistance.
Biomarkers identifying mCRPCs patients sensitive to Taxanes could have a major clinical impact and
improve patient care as well as the identification of novel therapeutic strategies. The aim of this PhD
was to identify, validate and clinically qualify predictive biomarkers of Taxane sensitivity while potentially
identifying new therapeutic strategies to reverse, or prevent the generation of Taxane resistance in
advanced prostate cancer. This aim was first investigated by thorough in vitro studies in Taxaneresistant and sensitive prostate cancer cell line models, including RNA/DNA studies, protein analysis
as well as morphological analysis. A resistance mechanism in preclinical cell line models validated in
prior investigations was identified as ABCB1, a well described Taxane resistance driver in vitro. While
the upregulation of ABCB1 has been proven to cause Taxane resistance in cell cultures of various
cancer types, an upregulation in PCa patients was not detected. Due to the discrepancy between cell
line and patient data revealed during these studies, resistance and sensitivity mechanisms were further
investigated in patient-derived ctDNA sequencing data from three randomized clinical trials. Crosscomparing these data with further in-house generated datasets led to the discovery of several
significantly associated Taxane-sensitvity genes, which have been subsequently investigated and validated in vitro.
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Language
eng
License start date
2024-06-17
Citation
2024
Publisher
Institute of Cancer Research (University Of London)