Abstract 3752: Nanoparticles delivery of a novel AKT/PDK1 inhibitor inhibits pancreatic cancer tumor growth

Abstract

Abstract AKT (protein kinase B), a pleckstrin homology (PH) lipid binding domain and a serine/threonine kinase containing protein is a key component of the phophatidylinositol-3-kinase (PtdIns3-K) cell survival signaling pathway which is activated in pancreatic cancers. In this study, we describe the effects of a novel inhibitor of AKT/PDK1 (PH-427) that binds to the PH domain of AKT (Ki = 2.67 ± 0.37 μM) and PDK1 (Ki = 5.20 ± 0.45 μM) [1] thus preventing its binding to PtIns-(3,4,5)P3 at the plasma membrane and subsequent activation of both kinases. PH-427 inhibits AKT/PDK1 activities at low micromolar concentrations in BxPC-3 (wt-KRAS) and not in MiaPaCa2 (mt-KRAS) human pancreatic cancer cell lines. Accordingly, we have shown that in vivo, PH-427 is poorly efficient in MiaPaCa2 xenografts as compared to BxPC-3 xenografts. In order to increase the potency and delivery of PH-427 to the tumor, we have encapsulated the compound (>10% of the compound) into (poly-d, l-lactide-co-glycolide) (PLGA) nanoparticles (PNP). We demonstrate that PH-427 incorporates well in the nanoparticles (PH-427-PNP) (<200 nm in size) and is slowly released from the polymer with a 90% released over a period of 30 days. We show that PH-427-PNP were very efficient in reducing MiaPaCa-2-Luc orthotopic pancreatic tumor growth as evaluated by luminescence using an AMI-1000 scanner. MiaPaCa2-Luc pancreas tumor volume was significantly reduced in animals treated with PH-427-PNP as compared to animal treated with PH-427 alone or the PNP alone (41.4±29.9 versus 2051±387 and 631±45 mm3). In conclusion, PH-427 alone did not alter tumor growth in MiaPaCa-2-Luc but was able to reduce tumor growth significantly when encapsulated in PNP. Finally and interestingly, metastasis to the liver and other organs was also significantly inhibited by PH-427-PNP as compared to PNP or PH-427 alone. [1]. Meuillet EJ, Ihle N, Lemos R, Moses SA, Song Z, Zhang S, Mash EA, Powis G (2010). Mol Cancer Ther 9(3):706-717. 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 3752. doi:1538-7445.AM2012-3752