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FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer

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Annett, Stephanie, Moore, Gillian, Short, Amy, Marshall, Andrea, McCrudden, Cian, Yakkundi, Anita, Das, Sudipto, McCluggage, W. Glenn, Nelson, Laura, Harley, Ian et al.
(2020) FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. British Journal of Cancer, 122 . pp. 361-371. doi:10.1038/s41416-019-0649-5 ISSN 0007-0920.

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Official URL: http://dx.doi.org/10.1038/s41416-019-0649-5

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Abstract

Background
ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours.

Methods
In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA).

Results
ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC.

Conclusion
FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
Q Science > QP Physiology
R Medicine > RC Internal medicine
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Ovaries -- Cancer , Ovaries -- Cancer -- Treatment, Vascular endothelial growth factors, Cancer cells , Stem cells
Journal or Publication Title: British Journal of Cancer
Publisher: Nature Publishing Group
ISSN: 0007-0920
Official Date: 4 February 2020
Dates:
DateEvent
4 February 2020Published
27 November 2019Available
29 October 2019Accepted
Volume: 122
Page Range: pp. 361-371
DOI: 10.1038/s41416-019-0649-5
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 4 December 2019
Date of first compliant Open Access: 27 May 2020
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
UNSPECIFIEDNorthern Ireland. Executive Officehttp://viaf.org/viaf/3684149662181707020002
UNSPECIFIEDAlmac Discoveryhttp://dx.doi.org/10.13039/501100003209
UNSPECIFIED[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
310670National Health and Medical Research Council (Australia)http://viaf.org/viaf/144832510
628903National Health and Medical Research Council (Australia)http://viaf.org/viaf/144832510
12/RIG/1-17Cancer Institute NSWhttp://dx.doi.org/10.13039/501100001171
15/RIG/1-16Cancer Institute NSWhttp://dx.doi.org/10.13039/501100001171

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