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

• Published in: British journal of cancer Vol. 122; no. 3; pp. 361 - 371
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2020; Nature Publishing Group
• Subjects: 631/67/2328; 631/67/71; 692/4028/67/1517/1709; Angiogenesis; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Ovarian Epithelial - blood supply; Carcinoma, Ovarian Epithelial - metabolism; Carcinoma, Ovarian Epithelial - pathology; CD44 antigen; Cell Differentiation - drug effects; Cell Line, Tumor; Drug Resistance; Enzyme-linked immunosorbent assay; Epidemiology; Female; Humans; Hyaluronan Receptors - drug effects; Hyaluronan Receptors - metabolism; Immunohistochemistry; In Vitro Techniques; Interleukin 6; Interleukin-6 - metabolism; Mice; Mice, SCID; Mimicry; Molecular Medicine; Neoplastic Stem Cells - drug effects; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Oncology; Ovarian cancer; Ovarian Neoplasms - blood supply; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Patients; Peptides; Peptides - pharmacology; Signal Transduction; Solid tumors; Stat3 protein; STAT3 Transcription Factor - drug effects; STAT3 Transcription Factor - metabolism; Stem cells; Tacrolimus Binding Proteins - drug effects; Tacrolimus Binding Proteins - metabolism; Tumors; Western blotting; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-019-0649-5

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.