Hyperleptinaemia is a well-established therapeutic side effect of drugs inhibiting
the androgen axis in prostate cancer (PCa), including main stay androgen deprivation
therapy (ADT) and androgen targeted therapies (ATT). Given significant crossover between
the adipokine hormone signalling of leptin and multiple cancer-promoting hallmark
pathways, including growth, proliferation, migration, angiogenesis, metabolism and
inflammation, targeting the leptin axis is therapeutically appealing, especially in
advanced PCa where current therapies fail to be curative. In this study, we uncover
leptin as a novel universal target in PCa and are the first to highlight increased
intratumoural leptin and leptin receptor (LEPR) expression in PCa cells and patients'
tumours exposed to androgen deprivation, as is observed in patients' tumours of metastatic
and castrate resistant (CRPC) PCa. We also reveal the world-first preclinical evidence
that demonstrates marked efficacy of targeted leptin-signalling blockade, using Allo-aca,
a potent, specific, and safe LEPR peptide antagonist. Allo-aca-suppressed tumour growth
and delayed progression to CRPC in mice bearing LNCaP xenografts, with reduced tumour
vascularity and altered pathways of apoptosis, transcription/translation, and energetics
in tumours determined as potential mechanisms underpinning anti-tumour efficacy. We
highlight LEPR blockade in combination with androgen axis inhibition represents a
promising new therapeutic strategy vital in advanced PCa treatment.
