Combination of lutetium-177 labelled anti-L1CAM antibody chCE7 with the clinically relevant protein kinase inhibitor MK1775: a novel combination against human ovarian carcinoma

Background Protein kinase inhibitors (PKIs) are currently tested in clinical studies (phase I-III) as an alternative strategy against (recurrent) ovarian cancer. Besides their anti-tumour efficacy, several PKIs have also shown radiosensitizing effects when combined with external beam radiation. Base...

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Bibliographic Details
Published in:BMC cancer Vol. 18; no. 1; pp. 922 - 14
Main Authors: Lindenblatt, Dennis, Terraneo, Nastassja, Pellegrini, Giovanni, Cohrs, Susan, Spycher, Philipp René, Vukovic, David, Béhé, Martin, Schibli, Roger, Grünberg, Jürgen
Format: Journal Article
Language:English
Published: London BioMed Central 25.09.2018
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
177Lu-radioimmunotherapy
Analysis
Animals
Antineoplastic Agents, Immunological - pharmacology
Apoptosis
Apoptosis - drug effects
Apoptosis - genetics
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer Research
Cancer therapies
Care and treatment
Cell cycle
Cell Line, Tumor
Cell Survival - drug effects
Clinical trials
Cyclin-dependent kinases
Cytotoxicity
Deoxyribonucleic acid
Disease Models, Animal
DNA
DNA Breaks, Double-Stranded - drug effects
DNA damage
DNA repair
Drug therapy
Enzyme inhibitors
Experimental therapeutics and drug development
Female
Flow cytometry
Growth inhibition
Health aspects
Health Promotion and Disease Prevention
Humans
Immunoconjugates - pharmacology
Immunohistochemistry
Kinases
L1CAM
Lutetium
mAb chCE7
Medical prognosis
Medicine/Public Health
Mice
MK1775 (AZD1775)
Monoclonal antibodies
Neural Cell Adhesion Molecule L1 - antagonists & inhibitors
Oncology
Ovarian cancer
Ovarian carcinoma
Phosphorylation
Protein kinase inhibitor
Protein kinase inhibitors
Protein Kinase Inhibitors - pharmacology
Protein kinases
Proteins
Pyrazoles - pharmacology
Pyrimidines - pharmacology
Radioimmunotherapy
Radioisotopes
Radioresistance
Research Article
Response rates
Surgical Oncology
Tumors
Xenograft Model Antitumor Assays
Xenografts
Lu-radioimmunotherapy
MK1775 (AZD1775)
Ovarian carcinoma
Protein kinase inhibitor
L1CAM
Combination therapy
mAb chCE7
177Lu-radioimmunotherapy
ISSN:1471-2407, 1471-2407
Online Access:Get full text
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Summary:Background Protein kinase inhibitors (PKIs) are currently tested in clinical studies (phase I-III) as an alternative strategy against (recurrent) ovarian cancer. Besides their anti-tumour efficacy, several PKIs have also shown radiosensitizing effects when combined with external beam radiation. Based on these results we asked if the addition of PKIs offers a therapeutic opportunity to improve radioimmunotherapy (RIT) against ovarian cancer. Five PKIs (alisertib, MK1775, MK2206, saracatinib, temsirolimus) were chosen for cytotoxicity screenings based on their current clinical trials in the treatment of ovarian cancer and their influence on cell cycle regulation and DNA damage repair pathways. We combined selected PKIs with 177 Lu-labelled anti-L1CAM monoclonal antibody chCE7 for our investigations. Methods PKIs cytotoxicity was determined via cell colony-forming assays. Biomarker of DNA double-strand breaks (DSBs, γH2A.X) was analysed by western blot and fluorescence microscopy. Flow cytometric measurements were performed to evaluate levels of apoptosis based on mono- or combination treatments. The best combination was used for in vivo combination therapy studies in nude mice with SKOV3ip and IGROV1 human ovarian cancer xenografts. Bonferroni correction was used to determine statistical significance for multiple comparisons. Results The highest cytotoxicity against both cell lines was observed for MK1775 and alisertib. Combinations including 177 Lu-labelled mAb chCE7 and MK1775 decreased 177 Lu-DOTA-chCE7 IC 60 -values 14-fold, compared to 6-fold, when the radioimmunoconjugate was combined with alisertib. The most effective PKI MK1775 was further evaluated and demonstrated synergistic effects in combination with 177 Lu-DOTA-chCE7 against IGROV1 cells. Significantly higher amounts of DSBs were detected in IGROV1 cells after combination (91%) compared to either treatment alone (MK1775: 52%; radioimmunoconjugate: 72%; p  < 0.0125). Early-apoptosis was significantly enhanced in IGROV1 cells correlating with induced DSBs ( 177 Lu-DOTA-chCE7: 8%, MK1775: 28%, 177 Lu-DOTA-chCE7 + MK1775: 40%, p  < 0.0125). Immunohistochemistry analysis of γH2A.X expression levels after therapy in SKOV3ip xenografts revealed a high sensitivity of the tumour cells to MK1775 and a high radioresistance. A prominent effect of tumour growth inhibition of the RIT and of the combination therapy was observed in vivo in a late stage IGROV1 xenograft model. Conclusions Our results warrant further evaluation of combination of MK1775 and radioimmunotherapy.
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ISSN:1471-2407
1471-2407
DOI:10.1186/s12885-018-4836-1