Abstract LB-66: NVP-BEZ235 and bevacizumab as therapy for glioblastoma

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 19_Supplement; p. LB-66
• Main Authors: Netland, Inger Anne, Førde, Hilde, Sleire, Linda, Skeie, Bente S., Enger, Per Øyvind, Goplen, Dorota
• Format: Journal Article
• Language: English
• Published: 01.10.2014
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-LB-66

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumour. Its dismal prognosis despite multimodal treatment comprising surgery, radiotherapy and chemotherapy, calls for new therapeutic strategies. GBM is a highly vascularized cancer, with elevated expression levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. Bevacizumab is a humanized anti-VEGF monoclonal antibody in clinical use as an angiogenesis inhibitor. Although bevacizumab is approved for treatment of GBM, several studies now show that it does not prolong survival. In addition, it has been shown that bevacizumab treatment leads to increased invasion and upregulation of gene transcripts involved in phosphoinositol-3-kinase (PI3K) - pathways. NVP-BEZ235 is a dual PI3K/mTOR kinase inhibitor. Combining NVP-BEZ235 with bevacizumab may therefore target both the angiogenic and invasive phenotype of GBMs.In vitro, the U-87 glioma cell line showed a dose-dependent reduction in cell proliferation to doses of NVP-BEZ235 from 0 to 250nM, as shown by direct cell count, BrdU incorporation and MTS assay. Furthermore, this was accompanied by a dose-dependent reduction of phosphorylated Akt at Serine 473, while the total levels of Akt remained unchanged. An IC50 of 11nM NVP-BEZ235 for the tumour material implanted, was determined in vitro by MTS assay. In order to validate combination treatment of BEZ235 and Avastin in vivo, we utilized a clinically relevant patient-based GBM xenograft model in NOD/SCID mice that mimics both the invasive and angiogenic growth pattern of human GBMs. In total 40 mice were allocated to four groups that received combination treatment with Avastin/BEZ235, monotreatment with Avastin or BEZ235 and untreated controls. Tumor engraftment and growth was confirmed and monitored longitudinally with MRI. The study is ongoing, survival data including histopathological analysis will be presented. Citation Format: Inger Anne Netland, Hilde Førde, Linda Sleire, Bente S. Skeie, Per Øyvind Enger, Dorota Goplen. NVP-BEZ235 and bevacizumab as therapy for glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-66. doi:10.1158/1538-7445.AM2014-LB-66