Camorani, Simona (2014) Inhibition of receptor signaling and of glioblastoma cell growth by a novel PDGFRβ aptamer. [Tesi di dottorato]

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: Inhibition of receptor signaling and of glioblastoma cell growth by a novel PDGFRβ aptamer
Autori:
AutoreEmail
Camorani, Simonasimicamo@libero.it
Data: 30 Marzo 2014
Numero di pagine: 134
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Oncologia ed endocrinologia molecolare
Ciclo di dottorato: 26
Coordinatore del Corso di dottorato:
nomeemail
Santoro, Massimomasantor@unina.it
Tutor:
nomeemail
de Franciscis, Vittorio[non definito]
Data: 30 Marzo 2014
Numero di pagine: 134
Parole chiave: aptamer; PDGFRβ; glioblastoma.
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Area 06 - Scienze mediche > MED/04 - Patologia generale
Aree tematiche (7° programma Quadro): SALUTE e TUTELA DEL CONSUMATORE > Biotecnologie, strumenti e tecnologie generiche per la salute umana
Depositato il: 12 Apr 2014 11:46
Ultima modifica: 15 Lug 2015 01:01
URI: http://www.fedoa.unina.it/id/eprint/9791

Abstract

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 β (PDGFRβ), 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 PDGFRβ. However, they are not selective as they present multiple tyrosine kinase targets, exhibiting modest efficacy. Thus, there is the urgent need to design new PDGFRβ-targeting drugs for a more specific and selective tumor therapy. Here, we report a novel PDGFRβ-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 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.

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