Abstract 2126: CA102N, a conjugate of hyaluronic acid (ha) and Nimuselide derivative (H-Nim) interferes with PI3K/Akt/mTOR signaling pathway in colorectal cancer (CRC) cells and inhibits tumor growth in vivo

Abstract

Abstract Aberrant PI3K/Akt/mTOR signaling pathway is common in several human cancers, including CRC. The pathway regulates many major cellular processes and promotes tumorigenesis and inhibition of apoptosis. Targeting the PI3K/Akt/mTOR network could be important in resistance mechanisms in cancer. CA102N, is a conjugate of Hyaluronic Acid (HA) and H-Nim, a nimuselide (COX-2 inhibitor) derivative, currently under investigation for preclinical development in CRC. Studies have suggested that the anti-proliferative effects of COX-2 inhibitors could be attributed to modulation of the PI3K/AKT signaling pathway; therefore, in this study we aimed to examine the overall molecular mechanism of the antitumor activity of CA102N and evaluate its impact on the PI3K pathway proteins. Cell based studies indicated that in addition to cell cycle arrest; the antitumor activity of CA102N is also related to apoptosis. Administration of CA102N to nude mice bearing established HT29 subcutaneous tumor xenografts caused significant tumor growth inhibition with no signs of systemic toxicity. Immunohistochemical analyses of xenograft tumors demonstrated inhibition of VEGF and CD31, suggesting a role for CA102N in angiogenesis. Disruption of angiogenesis and apoptosis was correlated with a decrease in VEGF and the antiapoptotic protein BCL-2. Suppression of PI3K downstream signaling was a key observation in HT29 cells in vitro and in xenograft tumors treated with CA102N. As compared to untreated vehicle control, a significant decrease in phosphorylation of AKT, mTOR, p70S6K, PRAS40, 4EBP1 and FOXO1 was detected by Western blot analyses. The reduction observed may be caused by both specific protein dephosphorylation/deactivation and by ubiquitin-mediated proteasomal degradation of pathway proteins. These results suggest that the antitumor activity of CA102N may be at least partly related to the modulation of the PI3K/Akt pathway proteins. CA102N represents a promising anticancer agent with minimal toxicity, the insights provided into the mechanisms of its anticancer activity may be the basis for advancing this candidate into clinic. Citation Format: Eskouhie H. Tchaparian, Louis Lin. CA102N, a conjugate of hyaluronic acid (ha) and Nimuselide derivative (H-Nim) interferes with PI3K/Akt/mTOR signaling pathway in colorectal cancer (CRC) cells and inhibits tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2126. doi:10.1158/1538-7445.AM2017-2126