FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer.
Animals
Carcinoma, Ovarian Epithelial
/ blood supply
Cell Differentiation
/ drug effects
Cell Line, Tumor
Female
Humans
Hyaluronan Receptors
/ drug effects
In Vitro Techniques
Interleukin-6
/ metabolism
Mice
Mice, SCID
Neoplastic Stem Cells
/ drug effects
Neovascularization, Pathologic
/ metabolism
Ovarian Neoplasms
/ blood supply
Peptides
/ pharmacology
STAT3 Transcription Factor
/ drug effects
Signal Transduction
Tacrolimus Binding Proteins
/ drug effects
Xenograft Model Antitumor Assays
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
05
04
2019
accepted:
29
10
2019
pubmed:
28
11
2019
medline:
21
10
2020
entrez:
28
11
2019
Statut:
ppublish
Résumé
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. 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). 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31772325
doi: 10.1038/s41416-019-0649-5
pii: 10.1038/s41416-019-0649-5
pmc: PMC7000737
doi:
Substances chimiques
FKBPL protein, human
0
Hyaluronan Receptors
0
Interleukin-6
0
Peptides
0
STAT3 Transcription Factor
0
Tacrolimus Binding Proteins
EC 5.2.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
361-371Subventions
Organisme : Medical Research Council
ID : G1001473
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_12021
Pays : United Kingdom
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