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Leptin antagonism inhibits prostate cancer xenograft growth and progression.

Authors :
Philp LK
Rockstroh A
Sadowski MC
Taherian Fard A
Lehman M
Tevz G
Libério MS
Bidgood CL
Gunter JH
McPherson S
Bartonicek N
Wade JD
Otvos L
Nelson CC
Source :
Endocrine-related cancer [Endocr Relat Cancer] 2021 Apr 29; Vol. 28 (5), pp. 353-375. Date of Electronic Publication: 2021 Apr 29.
Publication Year :
2021

Abstract

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.

Details

Language :
English
ISSN :
1479-6821
Volume :
28
Issue :
5
Database :
MEDLINE
Journal :
Endocrine-related cancer
Publication Type :
Academic Journal
Accession number :
33794502
Full Text :
https://doi.org/10.1530/ERC-20-0405