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.

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

“…As previously shown, the GL21.T and Gint4.T aptamers target and inhibit the Axl and the PDGFRβ receptors respectively [25,26]. While both Axl and the PDGFRβ receptors are expressed in U87MG, only PDGFRβ expression is strongly enhanced in tumor-spheres, compared to 2D cultured cells ( Supplementary Fig.…”

“…In our laboratory we have previously identified and characterized two internalizing RNA aptamers, GL21.T and Gint4.T, that are able to bind at high affinity and inhibit the intracellular signaling of tyrosine kinase receptors (RTKs) Axl and the platelet derived growth factor receptor β (PDGFRβ) respectively [25,26]. Axl and PDGFRβ overexpression has been reported in several human cancers and associated with invasiveness and therapeutic resistance [27,28].…”

“…1B). Moreover, both aptamers, GL21.T and Gint4.T, have been reported to interfere with cell migration [25,26]. As shown in Fig.…”

Aptamer for imaging and therapeutic targeting of brain tumor glioblastoma

“…This aptamer is promising for targeting the glioblastoma with this mutation. Besides that, it was shown to inhibit ligand-depending PDGFRb downstream signaling, which resulted in the inhibition of migration, proliferation and differentiation of cells in vitro and impairment of the tumor growth in vivo (25). Likewise, the aptamers designated U2, U8, 32, 41, 43, and 47 specifically binding to U87-MG EGFRvIII positive U87-MG cells, but not to nonmutated ones, were generated by the cell-SELEX method.…”

“…Camorani et al (25) used the platelet-derived growth factor receptor-beta (PDGFRb) for isolation and determination of aptamers specifically binding U87-MG cells. They utilized PDGFRb silenced U87-MG cells for negative selection.…”