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.