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https://wslhd.intersearch.com.au/wslhdjspui/handle/1/2724
Title: | FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer |
Authors: | Annett, S.;Moore, G.;Short, A.;Marshall, A.;McCrudden, C.;Yakkundi, A.;Das, S.;McCluggage, W. G.;Nelson, L.;Harley, I.;Moustafa, N.;Kennedy, Catherine J.;deFazio, Anna;Brand, Alison H.;Sharma, Raghwa;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. |
WSLHD Author: | Kennedy, Catherine J.;deFazio, Anna;Brand, Alison H.;Sharma, Raghwa |
Subjects: | Oncology |
Issue Date: | 2020 |
Citation: | British Journal of Cancer. 122(3):361-371, 2020 Feb |
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, qRTPCR, 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. |
URI: | https://wslhd.intersearch.com.au/wslhdjspui/handle/1/2724 |
DOI: | https://doi.org/10.1038/s41416-019-0649-5 |
Journal: | British Journal of Cancer |
Type: | Journal Article |
Study or Trial: | Controlled Study In Vitro Study |
Department: | Gynaecological Oncology |
Facility: | Blacktown Westmead Auburn |
Affiliated Organisations: | School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons Ireland, Dublin, Ireland School of Pharmacy, Queen's University Belfast, Belfast, UK Warwick Clinical Trials Unit, University of Warwick, Coventry, UK Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK Northern Ireland Gynaecological Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia The University of Sydney, Sydney, NSW, Australia NSW Health Pathology, ICPMR, Westmead, The University of Western Sydney, Westmead Hospital, Westmead, NSW, Australia UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland Department of Obstetrics and Gynaecology, School of Medicine, Trinity College Dublin, Dublin, Ireland Department of Histopathology, Trinity College Dublin, Dublin, Ireland Department of Histopathology, St. James's Hospital, Dublin, Ireland The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK The School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia |
Keywords: | carcinoma, ovarian animals peptides neoplastic stem cells |
Appears in Collections: | Blacktown Mount Druitt Hospital |
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Annett-2020-FKBPL-based peptide, ALM201, targe.pdf | 1.77 MB | Adobe PDF | ![]() View/Open |
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