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

Stephanie Annett; Gillian Moore; Amy Short; Andrea Marshall; Cian McCrudden; Anita Yakkundi; Sudipto Das; W Glenn McCluggage; Laura Nelson; Ian Harley; Nermeen Moustafa; Catherine J Kennedy; Anna deFazio; Alison Brand; Raghwa Sharma; Donal Brennan; Sharon O'Toole; John O'Leary; Mark Bates; Ciarán O'Riain; Darran O'Connor; Fiona Furlong; Helen McCarthy; Adrien Kissenpfennig; Lana McClements; Tracy Robson

doi:10.1038/s41416-019-0649-5

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

Stephanie Annett, Gillian Moore, Amy Short, Andrea Marshall, Cian McCrudden, Anita Yakkundi, Sudipto Das, W Glenn McCluggage, Laura Nelson, Ian Harley, Nermeen Moustafa, Catherine J Kennedy, Anna deFazio, Alison Brand, Raghwa Sharma, Donal Brennan, Sharon O'Toole, John O'Leary, Mark Bates, Ciarán O'RiainDarran O'Connor, Fiona Furlong, Helen McCarthy, Adrien Kissenpfennig, Lana McClements, Tracy Robson

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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.

Original language	English
Pages (from-to)	361
Journal	British Journal of Cancer
Volume	2020
Issue number	126
Early online date	27 Nov 2019
DOIs	https://doi.org/10.1038/s41416-019-0649-5
Publication status	Published - 04 Feb 2020

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FKBPL based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer
Copyright 2019 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 1.73 MBLicence: CC BY

Fiona Furlong
- f.furlongqub.acuk
- School of Pharmacy - Senior Lecturer
- Material and Advanced Technologies for Healthcare
Person: Academic

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Annett, S., Moore, G., Short, A., Marshall, A., McCrudden, C., Yakkundi, A., Das, S., McCluggage, W. G., Nelson, L., Harley, I., Moustafa, N., Kennedy, C. J., deFazio, A., Brand, A., Sharma, R., Brennan, D., O'Toole, S., O'Leary, J., Bates, M., ... Robson, T. (2020). FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. British Journal of Cancer, 2020(126), 361. https://doi.org/10.1038/s41416-019-0649-5

@article{679c3528f293454cad7b63d74049b202,

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

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.",

author = "Stephanie Annett and Gillian Moore and Amy Short and Andrea Marshall and Cian McCrudden and Anita Yakkundi and Sudipto Das and McCluggage, {W Glenn} and Laura Nelson and Ian Harley and Nermeen Moustafa and Kennedy, {Catherine J} and Anna deFazio and Alison Brand and Raghwa Sharma and Donal Brennan and Sharon O'Toole and John O'Leary and Mark Bates and Ciar{\'a}n O'Riain and Darran O'Connor and Fiona Furlong and Helen McCarthy and Adrien Kissenpfennig and Lana McClements and Tracy Robson",

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doi = "10.1038/s41416-019-0649-5",

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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 2020, 'FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer', British Journal of Cancer, vol. 2020, no. 126, pp. 361. https://doi.org/10.1038/s41416-019-0649-5

TY - JOUR

T1 - FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer

AU - Annett, Stephanie

AU - Moore, Gillian

AU - Short, Amy

AU - Marshall, Andrea

AU - McCrudden, Cian

AU - Yakkundi, Anita

AU - Das, Sudipto

AU - McCluggage, W Glenn

AU - Nelson, Laura

AU - Harley, Ian

AU - Moustafa, Nermeen

AU - Kennedy, Catherine J

AU - deFazio, Anna

AU - Brand, Alison

AU - Sharma, Raghwa

AU - Brennan, Donal

AU - O'Toole, Sharon

AU - O'Leary, John

AU - Bates, Mark

AU - O'Riain, Ciarán

AU - O'Connor, Darran

AU - Furlong, Fiona

AU - McCarthy, Helen

AU - Kissenpfennig, Adrien

AU - McClements, Lana

AU - Robson, Tracy

PY - 2020/2/4

Y1 - 2020/2/4

N2 - 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.

AB - 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.

U2 - 10.1038/s41416-019-0649-5

DO - 10.1038/s41416-019-0649-5

M3 - Article

C2 - 31772325

SN - 0007-0920

VL - 2020

SP - 361

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 126

ER -

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

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