Sabbatino, Francesco (2013) Counteracting resistance to chemo-radiotherapy and to targeted therapy in solid tumors. [Tesi di dottorato]
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tesi dottorato Sabbatino Francesco_25_FIN.pdf Download (7MB) | Anteprima |
| Tipologia del documento: | Tesi di dottorato | ||||||
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| Lingua: | English | ||||||
| Titolo: | Counteracting resistance to chemo-radiotherapy and to targeted therapy in solid tumors | ||||||
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| Data: | 31 Marzo 2013 | ||||||
| Numero di pagine: | 147 | ||||||
| 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: | 25 | ||||||
| Coordinatore del Corso di dottorato: |
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| Tutor: |
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| Data: | 31 Marzo 2013 | ||||||
| Numero di pagine: | 147 | ||||||
| Parole chiave: | 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 |
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| Aree tematiche (7° programma Quadro): | SALUTE e TUTELA DEL CONSUMATORE > Ottimizzazione per la prestazione delle cure sanitarie per i cittadini in Europa | ||||||
| Depositato il: | 11 Apr 2013 14:05 | ||||||
| Ultima modifica: | 17 Giu 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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