Abstract 5335: CA102N suppresses the growth of mouse colon cancer by inhibition of PI3K pathway and immune modulation

Abstract

Abstract It is well documented that COX-2 inhibitors have the potential in preventing or treating colorectal cancer. However, the cardiovascular toxicity of COX-2 inhibitors hampered further development of these inhibitors in cancer management. CA102N is a covalently bound conjugate of the biological polymer sodium hyaluronate (NaHA) and nimesulide (Nim) aiming to deliver Nim directly to the tumor tissues to limit the systemic toxicity. Here, we report the antitumor effect of CA102N in colon cancer and the possible mechanism associated with its antitumor activity. The antitumor efficacy of CA102N was tested in the CT-26 syngeneic Balb/c mouse colon cancer model. The effect of CA102N on inflammation was examined by serum cytokines, intratumor and urinary COX-2 metabolites. Immune modulation was determined by profiling TILs with flow cytometry. Cell signaling proteins were measured by western blot analysis. CA102N (50 mg/kg and 200 mg/kg) i.v. injected mice carrying CT26 mouse colon tumor showed significantly reduced average tumor weight (726.1 ± 335.2 mg and 633.4 ± 453.5 mg, respectively) compared to that of the vehicle control treated mice (1392.0 ± 523.8, p < 0.05). The reduction of tumor growth by CA102N in this particular tumor model was comparable to the mice having received TAS102 (100 mg/kg) p.o. daily for two weeks. Intratumor COX-2 metabolite analysis showed that CA102N (200 mg/kg) reduced levels of both PGE2 and PGI2 by 31% and 58% (p< 0.05), respectively compared to that of control group. The levels of urinary COX-2 metabolites in CA102N treated CT26 tumor bearing mice were similar to that of control mice. Results of serum cytokine analysis suggest that levels of MCP-1 (109.9 ± 24.3 pg/ml) and IL6 (18.0 ± 3.8 pg/ml) in CA102N (50 mg/kg) treated mice were significantly lower than that of control group (175.4 ± 21.0 pg/ml) and (123.3 ± 55.8 pg/ml), respectively (p < 0.05). Furthermore, TILs profiling showed that FOXP3+ T-regulatory immune cell population was reduced by almost 63% in CA102N (50 mg/kg) treated mice whereas the number of CD8+ T cells in CA102N (50 mg/kg) treated tumors was about 2-fold higher than that of the control group. In contrast, CA102N (200 mg/kg) treatment neither altered the serum cytokines and nor increased CD8+ T-cell populations in the tumor. Additionally, the protein expression of pAkt and pS6 in CA102N (200 mg/kg) treated tumor tissues were significantly down-regulated by more than 50% compared to that of control group, while CA102N (50 mg/kg) treatment only slightly altered the abundance of these proteins, suggesting antitumor activity of CA102N in different doses can potentially be mediated by differential mechanisms. Together, these findings suggest that the lower dose of CA102N exerts antitumor activity in mouse colon tumor model by immune modulation whereas the antitumor activity of the higher dose of CA102N might be mediated through inhibition of PI3kinase pathway on tumor tissues. Citation Format: Peiying Yang, Tara Conway, Patrea Rhea, Bo Wei, Eskouhie Tchaparian. CA102N suppresses the growth of mouse colon cancer by inhibition of PI3K pathway and immune modulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5335.