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 languageEnglish
Pages (from-to)361
JournalBritish Journal of Cancer
Volume2020
Issue number126
Early online date27 Nov 2019
DOIs
Publication statusEarly online date - 27 Nov 2019

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