Leptin antagonism inhibits prostate cancer xenograft growth and progression.

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:

17 Jan 2022 19:24

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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