THE INHIBITION OF ILK-1 INCREASES THE EFFICACY OF ANTI-ANGIOGENIC THERAPIES

The prognosis of the most common glial tumors, the glioblastoma (GBM; World Health Organization grade IV), remains poor with a 2-year survival rate in less than 20% of the patients despite significant advances in therapeutic options available. The dependence of tumor growth and metastasis on angiogenesis has provided powerful rationale for anti-angiogenic approaches to cancer therapy (Folkman J. 1971; Carmeliet P. et al. 2000). The main aim of this project was the characterization of tumour response to anti-angiogenic therapy and to find out new markers and better therapies to treat them. In a previous study we have demonstrated the role of Integrin Linked Kinase-1 (ILK-1), a kinase involved in cell cycle progression, inhibition of apoptosis, cell growth and migration, in the resistence of glioma to anti-angiogenic drugs. In fact, we found that the expression level of this protein decreases in the first part of the anti-angiogenic treatment and increases after 20 days of treatment in an in vivo model of glioblastoma. In addition we found that the expression levels of ILK-1 correlate with the worst outcome in patients. We demonstrated a strong reduction of tumour growth after the silencing of ILK-1 in our in vivo model. We want to analyze the effects of a small specific inhibitor of ILK-1: QLT0267 alone or in combination with two anti-angiogenic drugs already used in clinic: sorafenib and sunitinib that inhibit tyrosine kinase receptors. The combination of the pharmacologic inhibition of ILK-1 and angiogenesis lead to a significant decrease of tumour volume and vessels formation. We than investigated the molecular mechanism underling the effect of the combination of the inhibition of angiogenesis and ILK-1 studying what pathway is implicated. We speculate that the inhibition of tyrosine kinase receptors and the ILK-1 activity lead, through AKT pathway, to a downregulation of the pathways involved in angiogenesis. Interestingly, we found a strong decrease in glioma cells of HIF-1α protein after the combined treatments and we think that this can be related to the effects on vessel formation and on tumour growth that we have observed in vivo. Our data taken together indicate that the combinatorial administration of compounds that simultaneously inhibit angiogenesis and tumor cell proliferation by targeting specific signaling pathways might results in a significant increase in the therapeutic efficacy.