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

Research output: Contribution to journalArticle

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 languageEnglish
JournalBritish Journal of Cancer
Early online date27 Nov 2019
DOIs
Publication statusEarly online date - 27 Nov 2019

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Neoplastic Stem Cells
Ovarian Neoplasms
Peptides
Neoplasms
Heterografts
Interleukin-6
Colony-Forming Units Assay
Cell Line
Medical Oncology
Growth
Therapeutics
Western Blotting
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Clinical Trials
Polymerase Chain Reaction
Population
Proteins

Cite this

Annett, S., Moore, G., Short, A., Marshall, A., McCrudden, C., Yakkundi, A., ... Robson, T. (2019). FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. British Journal of Cancer. https://doi.org/10.1038/s41416-019-0649-5
Annett, Stephanie ; Moore, Gillian ; Short, Amy ; Marshall, Andrea ; McCrudden, Cian ; Yakkundi, Anita ; Das, Sudipto ; McCluggage, W Glenn ; Nelson, Laura ; Harley, Ian ; Moustafa, Nermeen ; Kennedy, Catherine J ; deFazio, Anna ; Brand, Alison ; Sharma, Raghwa ; Brennan, Donal ; O'Toole, Sharon ; O'Leary, John ; Bates, Mark ; O'Riain, Ciarán ; O'Connor, Darran ; Furlong, Fiona ; McCarthy, Helen ; Kissenpfennig, Adrien ; McClements, Lana ; Robson, Tracy. / FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. In: British Journal of Cancer. 2019.
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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.",
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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 2019, 'FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer', British Journal of Cancer. https://doi.org/10.1038/s41416-019-0649-5

FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. / Annett, Stephanie; Moore, Gillian; Short, Amy; Marshall, Andrea; McCrudden, Cian; Yakkundi, Anita; Das, Sudipto; McCluggage, W Glenn; Nelson, Laura; Harley, Ian; Moustafa, Nermeen; Kennedy, Catherine J; deFazio, Anna; Brand, Alison; Sharma, Raghwa; Brennan, Donal; O'Toole, Sharon; O'Leary, John; Bates, Mark; O'Riain, Ciarán; O'Connor, Darran; Furlong, Fiona; McCarthy, Helen; Kissenpfennig, Adrien; McClements, Lana; Robson, Tracy.

In: British Journal of Cancer, 27.11.2019.

Research output: Contribution to journalArticle

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 - 2019/11/27

Y1 - 2019/11/27

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

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

ER -