Investigation of anticancer activity of Recombinant OPCML (rOPCML) in ovarian cancer and glioblastoma cell lines


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Claudia von Arx1,Yuewei Xu1,Nelofer Syed1,Chiara Recchi1,Kevin O'Neill1,Manuela Mura1,Hani Gabra2
1Imperial College London,2Imperial College London - AstraZeneca

Abstract

Background

Receptor Tyrosine Kinases (RTKs) are aberrantly expressed and overactive in many cancer types causing tumour cell proliferation, invasion and resistance to chemotherapy. The use of targeted therapy has led to improved patient survival; however genetic mutations, and the activation of compensatory signalling pathways typically results in resistance to therapy. The use of multi-targeted or combination of single targeted RTKs inhibitors has proven to be an effective strategy in controlling RTK bypass redundancy at the cost of increased toxicity.

OPCML, a GPI anchored cell adhesion molecule is expressed in normal tissue and its expression is lost by somatic methylation in many cancer types. Its restoration causes the concurrent inhibition of multiple tyrosine kinases including HER2, AXL, cMET, FGFR, EphA2, leading to the inhibition of proliferation, migration, invasion, EMT and tumorigenicity in-vivo.

Method

The localization and site of action of OPCML in the raft fraction of the extracellular leaflet of the plasma membrane renders the use of recombinant OPCML (rOPCML) a viable therapeutic option, that of extracellular tumour suppressor therapy. HEK293 cells were used to produce rOPCML in its native structure and glycosylation pattern. Ovarian cancer and Gliobalstoma cell lines were used as a model for the investigation of rOPCML efficacy with a combination of proteomic and phenotypic assays.

Results

rOPCML therapeutic showed strong dephosphorylation of activated RTKs such as pAXL, pHer2 and pcMet and downstream effectors such as P-AKT and P-ERK1/2, in ovarian cancer cell lines (OVCAR8, SKOV3 and PEO4) and in the glioblastoma cell line U87MG. Moreover a dramatic decrease in tumour spheroid invasion in Matrigel®, cell viability and increase in apoptosis was also observed.

Conclusion

The preclinical in-vitro results from this study indicate that rOPCML is effective and specific in ovarian cancer and glioblastoma cell lines.