Hyperleptinemia 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 patient tumours exposed to androgen deprivation, as is observed in patient tumours of metastatic and castrate resistant (CRPC) PCa. We also reveal 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.

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