Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma.
This research aimed to find an immunotherapeutic target in neuroblastoma other than GD2 with low expression in normal tissue in order to develop new therapies that may be less toxic than dinituximab or to use in relapsed/refractory patients.
Publicly available RNA sequencing data from TARGET (high risk neuroblastoma) and GTeX (control) data were initially used. The group identified membrane-associated proteins highly expressed in neuroblastoma and not in normal tissues. Further studies were then done with the best target (GPC2) to validate its expression levels and to assess its role in neuroblastoma growth. Finally an antibody-cytotoxic conjugate was developed and tested both in cell lines and in a patient-derived xenograft murine model.
GPC2 protein was found to be expressed on the membrane in most neuroblastoma cell lines, tumors, and patient-derived xenografts but at varying levels. It was expressed at lower levels in the esophagus and skin but the tumour-associated protein was a different isoform. Tumors with MYCN amplification and 7q gain had high GPC2 expression. The protein was found to be essential for growth and proliferation of cell lines as was expected as it has been previously shown to be a growth factor receptor. An antibody conjugate against GPC2 was effective both in cell lines and in a patient-derived xenograft murine model. Interestingly, GPC2 is also highly expressed in medulloblastomas and retinoblastomas.
The antibody-drug conjugate hasn't yet been tested in humans and the pharmacokinetics may be different from those in mice.