FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer.
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.
Department of Employment and Learning, Northern Ireland
Almac Discovery Ltd.
MRC Proof of Concept grant
Australian National Health and Medical Research Council Enabling Grants ID 310670 and ID 628903
Cancer Institute NSW Grants ID 12/RIG/1–17 and 15/RIG/1–16
CommentsThe original article is available at https://www.nature.com/
Published CitationAnnett 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. British Journal of Cancer. 2020;122(3):361-371.
Publication Date27 November 2019
- School of Pharmacy and Biomolecular Sciences
- Irish Centre for Vascular Biology
- Vascular Biology
- Immunity, Infection and Inflammation
- Published Version (Version of Record)