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

Annett, S; Moore, G; Short, A; Marshall, A; McCrudden, C; Yakkundi, A; Das, S; McCluggage, WG; Nelson, L; Harley, I; Moustafa, N; Kennedy, CJ; deFazio, A; Brand, A; Sharma, R; Brennan, D; O’Toole, S; O’Leary, J; Bates, M; O’Riain, C; O’Connor, D; Furlong, F; McCarthy, H; Kissenpfennig, A; McClements, L; Robson, T

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

Annett, S Moore, G Short, A Marshall, A McCrudden, C Yakkundi, A Das, S McCluggage, WG Nelson, L Harley, I Moustafa, N Kennedy, CJ deFazio, A Brand, A Sharma, R Brennan, D O’Toole, S O’Leary, J Bates, M O’Riain, C O’Connor, D Furlong, F McCarthy, H Kissenpfennig, A McClements, L

Robson, T

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Publication Type:: Journal Article
Citation:: British Journal of Cancer, 2020, 122 (3), pp. 361 - 371
Issue Date:: 2020-02-04

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Field	Value	Language
dc.contributor.author	Annett, S	en_US
dc.contributor.author	Moore, G	en_US
dc.contributor.author	Short, A	en_US
dc.contributor.author	Marshall, A	en_US
dc.contributor.author	McCrudden, C	en_US
dc.contributor.author	Yakkundi, A	en_US
dc.contributor.author	Das, S	en_US
dc.contributor.author	McCluggage, WG	en_US
dc.contributor.author	Nelson, L	en_US
dc.contributor.author	Harley, I	en_US
dc.contributor.author	Moustafa, N	en_US
dc.contributor.author	Kennedy, CJ	en_US
dc.contributor.author	deFazio, A	en_US
dc.contributor.author	Brand, A	en_US
dc.contributor.author	Sharma, R	en_US
dc.contributor.author	Brennan, D	en_US
dc.contributor.author	O’Toole, S	en_US
dc.contributor.author	O’Leary, J	en_US
dc.contributor.author	Bates, M	en_US
dc.contributor.author	O’Riain, C	en_US
dc.contributor.author	O’Connor, D	en_US
dc.contributor.author	Furlong, F	en_US
dc.contributor.author	McCarthy, H	en_US
dc.contributor.author	Kissenpfennig, A	en_US
dc.contributor.author	McClements, L https://orcid.org/0000-0002-4911-1014	en_US
dc.contributor.author	Robson, T	en_US
dc.date.available	2020-05-27T19:04:45Z
dc.date.issued	2020-02-04	en_US
dc.identifier.citation	British Journal of Cancer, 2020, 122 (3), pp. 361 - 371	en_US
dc.identifier.issn	0007-0920	en_US
dc.identifier.uri	http://hdl.handle.net/10453/137191
dc.description.abstract	© 2019, The Author(s), under exclusive licence to Cancer Research UK. 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.	en_US
dc.relation.ispartof	British Journal of Cancer	en_US
dc.relation.isbasedon	10.1038/s41416-019-0649-5	en_US
dc.subject.classification	Oncology & Carcinogenesis	en_US
dc.title	FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.citation.volume	122	en_US
utslib.for	1112 Oncology and Carcinogenesis	en_US
utslib.for	1117 Public Health and Health Services	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
pubs.issue	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	122	en_US

Abstract:

© 2019, The Author(s), under exclusive licence to Cancer Research UK. 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.

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http://hdl.handle.net/10453/137191