Leptin Receptor Antagonist, Allo-Aca, Inhibits Androgen-Deprived Prostate Cancer Cell Invasiveness In Vitro & Hinders Prostate Cancer Xenograft Progression In Vivo

Androgen deprivation therapy (ADT), the mainstay treatment in advanced prostate cancer (PCa), triggers Metabolic Syndrome-like side-effects, including elevated serum leptin. Using transcriptomics, we unveiled that ADT markedly upregulates leptin (LEP) & its receptor (LEPR) in vitro. Leptin reportedly promotes proliferation & migration in androgen-replete PCa cells, & intrinsically plays a role in inflammation & angiogenesis. Consequently, we hypothesise that leptin is implicated in PCa progression. This study therefore aimed to assess efficacy of LEPR antagonist Allo-aca (AA), in PCa cells subjected to ADT in vitro & in vivo. In vitro, androgen-deprived LNCaP & C4-2B were treated with leptin (0-20nM) ± AA (0-100nM); effect on proliferation, migration & invasion were assessed. In vivo, pilot efficacy of AA (sc 1mg/kg/d) in castrate Nude mice bearing sc LNCaP xenografts (vs saline) was determined. Leptin increased migration (vs control, P<0.05); this was prevented by AA (vs leptin, P<0.05). Leptin induced 3D-invasion; AA prevented invasive projections. Effects on proliferation were limited in vitro. In vivo (pilot), AA tended to prevent tumour growth; AA-treated tumours had lower mass (P=0.078) & volume (P=0.057), vs saline. Altered tumour phenotype & microenvironment were observed; AA-treated xenografts were paler than controls that were typically bloody & vascularised. Histopathology confirmed lower vascularity & blood infiltration with AA. Leptin fosters an aggressive PCa phenotype in vitro. In vivo AA suppressed tumour growth in a murine model of PCa progression & ADT adaptation. We speculate that suppression of angiogenesis may be causative. Our data highlight that AA may be a promising therapeutic in treating advanced PCa