Leptin antagonism inhibits prostate cancer xenograft growth and progression

in Endocrine-Related Cancer
Authors:
Lisa K Philp Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Anja Rockstroh Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Martin C Sadowski Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Atefeh Taherian Fard Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Melanie Lehman Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Gregor Tevz Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Michelle S Libério Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Charles L Bidgood Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Jennifer H Gunter Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Stephen McPherson Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Nenad Bartonicek Garvan Institute of Medical Research, Sydney, New South Wales, Australia

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John D Wade Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
School of Chemistry, University of Melbourne, Melbourne, Victoria, Australia

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Laszlo Otvos OLPE, LLC, Audubon, Pennsylvania, USA
Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary

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Colleen C Nelson Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia

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Correspondence should be addressed to L K Philp: lisa.philp@qut.edu.au
DOI:
https://doi.org/10.1530/ERC-20-0405
Volume/Issue:
Volume 28: Issue 5
Article Type:
Research Article
Page Range:
353–375
Online Publication Date:
29 Apr 2021
Copyright:
© 2021 Society for Endocrinology 2021
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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.

Supplementary Materials

    • Suppl Fig1. Human transcripts (tumour-specific) from Allo-aca (Allo) and Vehicle (Veh) treated tumors cluster separately in PCA plots of normalized CPM of human transcripts, COA plots of normalized CPM of human transcripts and PCA plots of normalized logCPM of differentially expressed (DE) human transcripts. 1448 DE human transcripts were observed with Allo-aca treatment.
    • Suppl Fig2(A-E). Allo-aca efficacy in LNCaP xenograft progression model in castrate Nude mice. Progression over time of (A) tumor xenograft volume from day 0 and (B) serum PSA from castration. Regression over time of (C) tumor volume and (D) serum PSA in the Allo regression cohort n=5). (E) Correlation of endpoint tumor PSA and volume. Cx = castration.
    • Suppl Fig3. Impact of leptin and Allo-aca on LNCaP cell LEPR protein. Representative images of LEPR (green) protein by immunofluorescence in LNCaP cells treated with acute leptin (10 nM) and Allo-aca (100 nM) in vitro under androgen deplete (CSS) or rich (FBS) conditions. Graphically represented as overall LEPR intensity of cells as calculated by Cell Profiler analysis. Statistics: **P≤0.01, ***P≤0.001 vs vehicle; #P≤0.05, ###P≤0.001 vs leptin alone in that condition.
    • Suppl Figure 4 (A-B). Effect of Allo-aca on tumor xenograft phenotype and migration. (A) MetaboAnalyst gene-centric pathway analysis showing significant enrichment of pathways associated with cell adhesion/motility in Allo-aca treated tumours. Analysis was performed on differentially expressed transcripts mapping to the human genome. Pathways are indicated by numbers alongside green circled nodes on the graph and details seen in the corresponding table. Node size corresponds to impact score while node colour corresponds to -log10P significance. (B) Effect of leptin and Allo-aca on androgen-deprived PCa cell transwell migration in vitro. Relative number of migrating LNCaP and C4-2B cells following androgen-deprivation and treatment with leptin doses (0, 2.5, 10 nM), and leptin doses + Allo-aca (1, 10, 100nM); expressed relative to ADT vehicle control. n=3; Statistics: *P<0.05, ***P<0.001, ****P<0.0001, vs ADT vehicle; tP=0.055-0.10, #P<0.05, ##P<0.01, ###P<0.001, vs leptin dose alone.
    • SupplTable1. Top 25 expressed transcripts (based on fpkm value from RNAseq) mapping to the mouse genome expressed in tumour xenografts in Allo-aca (Allo) and Vehicle (Veh) treated mice. Mitochondrial transcripts &#x2013; cell shaded grey. Transcript ID in superscript following gene symbol.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
23
Received Date:
19 Mar 2021
Accepted Date:
31 Mar 2021
Print Publication Date:
01 May 2021
Online Publication Date:
29 Apr 2021
Keywords:
leptin receptor antagonist; Allo-aca; prostate cancer; leptin; peptide drug

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