Leptin antagonism inhibits prostate cancer xenograft growth and progression

Abstract

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.

Targeting of Notch, IL-1, and leptin has therapeutic potential in xenograft colorectal cancer

“…To characterize the in vivo antitumor activity of DAPT, Anakinra and Allo aca, the tumor volume and body weight of the HCT-15 tumor-bearing mice was monitored. Initially, we determined the dose and duration of treatment based on previous in vivo studies ( Harnack et al, 2010 ; Otvos et al, 2011 ; Kalantari et al, 2013 ; Pilot et al, 2020 ; Philp et al, 2021 ). Based on this dose and duration information, we followed 15 days of treatment, twice a week, as described in the method, for CRC xenograft experiments.…”

Mendelian randomization evidence based on European ancestry for the causal effects of leukocyte telomere length on prostate cancer

“…The potential mediators we selected for further analysis and reasons for the selection, which are mainly based on previous research, are summarized in Table S15 . The physical indices included liver iron content [ 32 , 33 ], body fat percentage [ 34 ], sex hormone binding globulin levels [ 35 , 36 ], circulating leptin levels [ 37 , 38 ], mean corpuscular hemoglobin [ 39 ], and arm fat percentage (left and right) [ 40 ]. The nutritional component contains total fatty acids [ 41 ], polyunsaturated fatty acids [ 42 ], saturated fatty acids [ 43 ], vitamin D [ 44 ], vitamin E [ 45 ], and fresh tomato intake [ 46 ].…”

Periprostatic Adipose Tissue: A New Perspective for Diagnosing and Treating Prostate Cancer

“…Leptin activation induces PCa cancer proliferation, promote invasion, and inhibit apoptosis 122 . Philp et al further validated that the leptin receptor antagonist Alloaca inhibited LNCaP xenograft tumor growth, delayed progression to CRPC in mice, and suggested that leptin receptor blockade combined with androgen axis inhibition is a promising new therapeutic strategy for treating advanced PCa 123 . Hu et al found that patients with PCa had lower serum lipocalin.…”