BBB Seminar: Martha Chekenya
Preclinical validation of targeting NG2/MPG as a therapy for human brain tumours
Department of Biomedicine, University of Bergen
Initial observations indicated that the Neuron-Glia-2 (NG2) chondroitin sulphate proteoglycan was highly expressed in high-grade tumours, glioblastoma multiforme (GBM, grade IV), compared to the lower grade tumours and the normal brain. Since then my research over the last 13 years has been focused on elucidating NG2´s role in the malignant progression of human brain tumours. We have established that NG2 increased the proliferative and angiogenic potential of GBM cells in vitro and in animal studies. We have since shown that high NG2 expression is associated with resistance to chemotherapy in patient biopsy spheroids, cell lines and animals models of GBM. The mechanisms of resistance involved augmented integrin mediated activation of the PI3K/AKT survival signalling pathways.
Recent studies have been focused on establishing whether NG2 expression may be of prognostic significance in a large population of GBM patients. Our recent data showed a correlation of high NG2 expression in tumour cells or their associated vasculature with poorer survival outcomes. We are currently investigating whether NG2 is a single prognostic factor or whether other known factors such as the presence or absence of the methylguanine methyl transferase (MGMT) DNA repair gene, age, proliferation (by ki67 labelling index) and angiogenesis (by microvascular density counts) may be co-prognostic indicators. Preliminary data show that in 2/3 of the NG2 expressing GBMs, the MGMT promoter is silenced by methylation. So our hypothesis is that heightened survival signalling in the NG2 expressing tumours may rescue cells from the otherwise lethal DNA damage. Further studies are ongoing to investigate the genes involved in survival signalling that may be induced in response to chemotherapy. Since the MGMT status is also important for response to radiation therapy, we aimed to identify proteins that are differentially expressed in the high NG2 expressing tumours that may elucidate the mechanisms for the patients´ poorer survival outcomes. 2D-gel proteomics and MS/MS identified that peroxiredoxin (PRX-1), an endogenous antioxidant, is upregulated in the high NG2 expressing GBM biopsies compared to the low NG2 expressors. Further in vitro and in vivo studies in mice are underway to establish the association between NG2, PRX-1 and radiation response in the GBM samples.
So far both our previous and current data point towards NG2 being an important factor in GBM malignant progression. Since the normal brain has only restricted expression of this protein, NG2 may be an amenable therapeutic target. Our final aim is to target NG2 with monoclonal antibodies in combination with adoptively transferred, in vitro activated natural killer (NK) cells into the tumour-bed. Initial data from these studies using this immunotherapy approach are highly promising.
Chair: Rolf Bjerkvig, Department of Biomedicine