Abstract
Prostate Cancer (PCa) is the most common cancer in men, accounting for 7% of all cancer
deaths. The Androgen Receptor (AR) is a main driver of PCa, playing a significant role in the
progression and development of the disease and therefore therapies to combat its signalling
are standard-of-care treatments in the clinic. Androgen deprivation therapy (ADT) aims to
reduce free androgens to castration levels to quell AR signalling; however, failure of ADT often
leads to the progression of disease to Castration Resistant Prostate Cancer (CRPC).
Therapeutic options for CRPC are limited and mostly palliative, whereby further resistance
mechanisms often occur and therefore improvements of treatments are paramount for the
quality of life for patients. A resistant tumour phenotype is often as a consequence of
dysregulation of AR signalling due to treatment selection pressure against hormone therapies
such as Enzalutamide. These are often mutations in the AR which cause increased copy
numbers of the AR gene and thus protein, receptor promiscuity caused by gain-of-function
mutations with the Ligand-binding domain (LBD) or the emergence of constitutively active AR
Variants. Currently, the mechanisms of hormone therapy resistance are not fully understood
and there are no standard-of-care therapies against the AR mutants.
This thesis aims to understand the different clinical presentations of hormone therapy
resistance and tests the efficacy of novel dual-targeting AR inhibitors for the treatment of
CRPC.