Inhibition of receptor signaling and of glioblastoma cell growth by a novel PDGFR? aptamer

Glioblastoma multiforme is the most common and lethal primary human brain tumor. Despite aggressive treatment, including surgery, adjuvant temozolomide-based chemotherapy, and radiotherapy, glioblastoma still has a dismal prognosis. Platelet-derived growth factor receptor ? (PDGFR?), a cell-surface tyrosine kinase receptor, is an important hallmark involved in glioma since it influences several cellular processes of tumor biology including proliferation, migration, and angiogenesis. It represents a compelling therapeutic target in glioma. A number of tyrosine kinase inhibitors under development as antitumor agents have been found to inhibit PDGFR?. However, they are not selective as they present multiple tyrosine kinase targets, exhibiting modest efficacy. Thus, there is the urgent need to design new PDGFR?-targeting drugs for a more specific and selective tumor therapy. Here, we report a novel PDGFR?-specific antagonist represented by a nuclease-resistant RNA-aptamer, named Gint4.T. Aptamers, thanks to their unique characteristics (low size, good target affinity, no immunogenicity, high stability), represent a new class of molecules with a great potential to rival monoclonal antibodies in both therapy and diagnosis. Gint4.T aptamer is able to specifically bind to the human PDGFR? ectodomain (Kd: 9.6 nmol/l) causing a strong inhibition of ligand-dependent receptor activation and of downstream signaling in cell lines and primary cultures of human glioblastoma cells. Moreover, Gint4.T aptamer drastically inhibits cell migration and proliferation, induces differentiation, and blocks tumor growth in vivo. In addition, Gint4.T aptamer prevents PDGFR? heterodimerization with and resultant transactivation of epidermal growth factor receptor. As a result, the combination of Gint4.T and an epidermal growth factor receptor†"targeted aptamer is better at slowing tumor growth than either single aptamer alone. These findings reveal Gint4.T as a PDGFR?-drug candidate with translational potential.