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

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posted on 19.02.2021, 10:03 by 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

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.

Funding

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

History

Comments

The original article is available at https://www.nature.com/

Published Citation

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. FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. British Journal of Cancer. 2020;122(3):361-371.

Publication Date

27 November 2019

PubMed ID

31772325

Department/Unit

  • School of Pharmacy and Biomolecular Sciences
  • Irish Centre for Vascular Biology

Research Area

  • Vascular Biology
  • Cancer
  • Immunity, Infection and Inflammation

Publisher

Springer Nature

Version

  • Published Version (Version of Record)

Licence

Exports