Abstract 5719: Improvement of radiotherapy for glioblastoma by co-targeting PI3K and HSP90
| Autor: | Richard Yaacov Lawrence, Adam P. Dicker, Yi Liu, Barbara Andersen, Phyllis R. Wachsberger |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Cancer Research. 72:5719-5719 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2012-5719 |
| Popis: | Introduction: Glioblastoma (GBM) tumors frequently contain mutations in the tumor suppressor gene, PTEN, leading to loss of PTEN activity. PTEN loss causes overactivation of the PI3K pathway, inducing inhibition of apoptosis and radioresistance. Heat-shock protein 90 (HSP90) is a molecular chaperone that is over-expressed in GBM and that has among its client proteins, PI3K and Akt. It was hypothesized that dual inhibition of Hsp90 and PI3K signaling would additively or synergistically radiosensitize GBM through inhibition of radiation-induced PI3K/Akt signaling, leading to enhanced apoptosis. This study investigated the radiosensitizing effect of the HSP 90 inhibitor, HSP990 in combination with the PI3K inhibitor, BKM-120 in U87 GBM xenografts. Methods: Human U87 (GBM) cells, null for PTEN, were studied. Radiosensitivity was determined by apoptotic assays (Annexin V kit) in vitro and by tumor growth delay studies in vivo. Immunoblots were performed to assess pAkt levels. HSP990 and BKM 120 were provided by Novartis Pharmaceuticals. Results: Apoptotic assays revealed the following percentages of cells undergoing apoptosis 48 hrs after treatments: radiation alone: 57%; HSP990 alone: 75%; HSP990 + radiation (RT): 86%; BKM120 alone: 59%; BKM120+ RT: 42%. The combination of BKM120 + HSP990 induced the highest percentage of apoptosis (89% of cell population). The addition of radiation to the combined drug treatment did not increase the percentage of cells undergoing apoptosis (66% for triple modality treatment vs. 89% for HSP990 + BKM120 treatment). In vivo, each individual treatment (RT, HSP990 or BKM120) slowed the rate of tumor growth compared with the control group and all pairs of treatments performed better than either of the component treatments alone (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5719. doi:1538-7445.AM2012-5719 |
| Databáze: | OpenAIRE |
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