Sabbatino, Francesco (2013) Counteracting resistance to chemo-radiotherapy and to targeted therapy in solid tumors. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Counteracting resistance to chemo-radiotherapy and to targeted therapy in solid tumors
Creators:
CreatorsEmail
Sabbatino, Francescosabbatino.francesco@alice.it
Date: 31 March 2013
Number of Pages: 147
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Oncologia ed endocrinologia molecolare
Ciclo di dottorato: 25
Coordinatore del Corso di dottorato:
nomeemail
Santoro, Massimomassimo.santoro@unina.it
Tutor:
nomeemail
Pepe, Stefanospepe@unisa.it
Ferrone, Soldanosferrone@partners.org
Date: 31 March 2013
Number of Pages: 147
Uncontrolled Keywords: BRAF inhibitor, resistance, sunitinib, imatinib, PDGFRα, melanoma
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Area 06 - Scienze mediche > MED/05 - Patologia clinica
Area 06 - Scienze mediche > MED/06 - Oncologia medica
Area 06 - Scienze mediche > MED/08 - Anatomia patologica
Area 06 - Scienze mediche > MED/26 - Neurologia
Area 06 - Scienze mediche > MED/27 - Neurochirurgia
Area 06 - Scienze mediche > MED/35 - Malattie cutanee e veneree
Aree tematiche (7° programma Quadro): SALUTE e TUTELA DEL CONSUMATORE > Ottimizzazione per la prestazione delle cure sanitarie per i cittadini in Europa
Date Deposited: 11 Apr 2013 14:05
Last Modified: 17 Jun 2014 06:04
URI: http://www.fedoa.unina.it/id/eprint/9294

Abstract

Control of mutant BRAF (V600E) metastatic melanomas by the selective BRAF inhibitor (BRAF-I), vemurafenib, is limited by the the lack of complete response due to intrinsic resistance and the often rapid development of acquired resistance . By utilizing melanoma cell lines with acquired BRAF-I resistance, we demonstrate for the first time an association between BRAF-I resistance and PDGFRα upregulation in vitro and in vivo. PDGFRα inhibition by PDGFRα-specific shRNA restores melanoma cells’ sensitivity to BRAF-I in vitro. These effects are mediated by inhibition of ERK and AKT activation, which is associated with BRAF-I resistance. Combining vemurafenib with a PDGFRα inhibitor (sunitinib or imatinib) in vitro and in vivo demonstrate a significantly greater anti-proliferative and pro-apoptotic effect than either agent individually. These effects reflect the inhibition of ERK and AKT activation, which inhibits the proliferation and induces apoptosis. We corroborated this finding by demonstrating PDGFRα upregulation in melanomas harvested from patients who demonstrated disease progression following treatment with BRAF-I. Furthermore, analysis of matched biopsies of BRAF-I treated melanoma patients before treatment, after 1-2 weeks of treatment and at the time of disease progression demonstrated that PDGFRα upregulation correlated with less tumor regression (based on RECIST criteria) and a shorter time to disease progression. Our results demonstrate that PDGFRα inhibitors (sunitinib or imatinib) in combination with vemurafenib can overcome BRAF-I resistance mediated by PDGFRα. Although we could not associate baseline PDGFRα with clinical outcome, our data suggest that monitoring patients for early up regulation of PDGFRα may identify those for whom combination therapy would be most appropriate.

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