title: Inhibition of receptor signaling and of glioblastoma-derived tumor growth by a novel PDGFRβ aptamer.
abstract: Platelet-derived growth factor receptor β (PDGFRβ) is a cell-surface tyrosine kinase receptor implicated in several cellular processes including proliferation, migration, and angiogenesis. It represents a compelling therapeutic target in many human tumors, including glioma. A number of tyrosine kinase inhibitors under development as antitumor agents have been found to inhibit PDGFRβ. However, they are not selective as they present multiple tyrosine kinase targets. Here, we report a novel PDGFRβ-specific antagonist represented by a nuclease-resistant RNA-aptamer, named Gint4.T. This aptamer is able to specifically bind to the human PDGFRβ 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 PDGFRβ 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 PDGFRβ-drug candidate with translational potential.
authors.affiliation: 1] Istituto di Endocrinologia e Oncologia Sperimentale "G. Salvatore", CNR, Via S. Pansini 5, Naples, Italy [2] Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Via S. Pansini 5, Naples, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Camorani
authors.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale "G. Salvatore", CNR, Via S. Pansini 5, Naples, Italy.
authors.forename: Carla L
authors.initials: CL
authors.lastname: Esposito
authors.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale "G. Salvatore", CNR, Via S. Pansini 5, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rienzo
authors.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale "G. Salvatore", CNR, Via S. Pansini 5, Naples, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Catuogno
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Via S. Pansini 5, Naples, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Iaboni
authors.affiliation: 1] Istituto di Endocrinologia e Oncologia Sperimentale "G. Salvatore", CNR, Via S. Pansini 5, Naples, Italy [2] Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Via S. Pansini 5, Naples, Italy.
authors.forename: Gerolama
authors.initials: G
authors.lastname: Condorelli
authors.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale "G. Salvatore", CNR, Via S. Pansini 5, Naples, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: de Franciscis
authors.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale "G. Salvatore", CNR, Via S. Pansini 5, Naples, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cerchia
mesh_terms: D052157:Aptamers, Nucleotide / Q000235:genetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000627:therapeutic use; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000628:therapy; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000627:therapeutic use; D015398:Signal Transduction / Q000235:genetics
chemical_list: D052157:Aptamers, Nucleotide; D066246:ErbB Receptors; D020797:Receptor, Platelet-Derived Growth Factor beta