Philp, Lisa K; Rockstroh, Anja; Sadowski, Martin C; Taherian Fard, Atefeh; Lehman, Melanie; Tevz, Gregor; Libério, Michelle S; Bidgood, Charles L; Gunter, Jennifer H; McPherson, Stephen; Bartonicek, Nenad; Wade, John D; Otvos, Laszlo; Nelson, Colleen C (2021). Leptin antagonism inhibits prostate cancer xenograft growth and progression. Endocrine-related cancer, 28(5), pp. 353-375. BioScientifica Ltd. 10.1530/ERC-20-0405
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Pathology |
UniBE Contributor: |
Sadowski, Martin |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
1351-0088 |
Publisher: |
BioScientifica Ltd. |
Language: |
English |
Submitter: |
Christa Hagert |
Date Deposited: |
06 Dec 2021 10:37 |
Last Modified: |
05 Dec 2022 15:55 |
Publisher DOI: |
10.1530/ERC-20-0405 |
PubMed ID: |
33794502 |
Uncontrolled Keywords: |
Allo-aca leptin leptin receptor antagonist peptide drug prostate cancer |
BORIS DOI: |
10.48350/161800 |
URI: |
https://boris.unibe.ch/id/eprint/161800 |
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