In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 579-579
Abstract:
Constitutive activation of the PI3K pathway is driven by a variety of genetic and epigenetic abnormalities, such as PTEN deletions, mutations, genesilencing, PIK3CA mutations and/or enhanced engagement through genetic abnormalities in upstream RTKs. Targeted therapies against specific components of the PI3K pathway are therefore expected to produce positive outcome as single agents or in combination in cancers presenting these abnormalities. Two molecular entities are in full clinical development: NVP-BEZ235, a dual PI3K/mTOR inhibitor and NVP-BKM120, a pan-class I PI3K inhibitor without mTOR activity. In order to best position these agents clinically, we investigated their efficacy in models bearing PIK3CA, PTEN, HER2, or KRAS genetic alterations. We previously demonstrated that NVP-BEZ235 in in vitro antiproferative activity was not predictive of preclinical antitumor response, in vivo. However, breast cancer models presenting either HER2 amplification or PIK3CA mutations or both were shown to be very sensitive to the compound and the use of cell death induction as an end-point was found to be predictive of strong antitumor activity in vivo. To further validate this finding, dual PI3K/mTOR targeting was phenocopied using an mTOR shRNA inducible system or an mTOR specific inhibitor (AZD8055) in combination with a pan-PI3K inhibitor, in various tumor models. Strong cell death signals were observed in 2 HER2 amplified / PIK3CA mutant breast cancer models but not in KRAS mutant cells or as PTEN silenced breast cancer cell lines, when subjected of PI3K/mTOR targeting. Moreover, in vivo, combination of a pure pan-PI3K with a pure mTOR inhibitor resulted in strong regression of HER2 amplified /PIK3CA mutant MDA-MB361 tumors.On the basis of these observations, NVP-BEZ235 was retested in a set of more then 150 tumor lines across various lineages, and cell death induction was determined. As expected, HER2 amplified /PIK3CA mutant breast cancer lines scored as sensitive. Other models from different indications and genetic background were also found to be sensitive to NVP-BEZ235. Validation studies of these new models and potential indications will be presented, and implications for further clinical trials of dual PI3K/mTOR or pure PI3K inhibitors discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 579. doi:10.1158/1538-7445.AM2011-579
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-579
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
