Abstract B190: GDC-0068 is a novel and selective Akt inhibitor that enhances the efficacy of FOLFOX in primary gastric cancer models.

Abstract

Abstract Background: Akt, a serine/threonine protein kinase, is a key signaling node in the PI3K/Akt/mTOR pathway and plays an essential role in regulating tumor cell proliferation, migration and survival. PI3K/Akt signaling is up-regulated in gastric cancer, mainly due to loss of PTEN, and is associated with poor prognosis and chemoresistance. Chemotherapeutics such as doxorubicin and 5-FU/cisplatin have been shown to upregulate PI3K/Akt signaling in several solid cancers in response to DNA damage. We have previously reported on a potent highly selective ATP-competitive pan-Akt inhibitor, GDC-0068, which inhibits cell cycle progression and viability of cancer cell lines and xenografts driven by Akt signaling, including those with defects in the tumor suppressor PTEN, oncogenic mutations in PIK3CA, and amplification of HER2. Thus, we hypothesized that the combination of FOLFOX and GDC-0068 would induce anti-tumor activity in primary gastric cancer models. Methods: Gastric cancer cell lines (n=11) were treated with increasing concentrations of GDC-0068 and FOLFOX and evaluated for combinational efficacy over single agent via cell viability assay. For in vivo studies, primary gastric cancer xenograft models were implanted in immuno-compromised mice and treated with GDC-0068 and FOLFOX as single agents or in combination. Results: In vitro, the combination of GDC-0068 and FOLFOX results in enhanced inhibition of tumor cell viability in the cell lines with activation of the PI3K pathway compared to either single agent alone. These results were recapitulated in vivo, in the primary xenograft models STO#240 and STO#182, where the combination of GDC-0068 and FOLFOX resulted in increased tumor growth inhibition or regressions compared to single agents alone. All combinations tested were well tolerated in vivo based on minimal changes in body weights. Conclusions: Our preclinical studies demonstrate improved anti-tumor efficacy when GDC-0068 is combined with FOLFOX in gastric cancer models in vitro and in vivo. The data supports the clinical development of GDC-0068 in combination with FOLFOX for the treatment of gastric cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B190. Citation Format: Ellen Ingalla, Rebecca Hong, Heidi Savage, Elizabeth Punnoose, Sandra Rost, Hartmut Koeppen, Deepak Sampath, Michelle A. Nannini. GDC-0068 is a novel and selective Akt inhibitor that enhances the efficacy of FOLFOX in primary gastric cancer models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B190.