Abstract 1916: Targeting adhesion signaling network blocks tumor growth in gallbladder cancer

Abstract

Abstract 96 Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Gallbladder cancer (GBC) is a highly fatal malignancy with a 5-year survival rate of 17.6%. The prognosis of GBC is poor due to the aggressive tumor biology, late presentation, complicated anatomic position, and advanced stage at diagnosis. Characterized by a poor response to chemotherapy and radiotherapy, locally advanced and metastatic disease in patients with GBC is often treated with chemotherapy with palliative purpose. Therefore, development of new effective therapies is urgently needed for the treatment of GBC. The aim of the current study is to evaluate whether triptolide and its water soluble analog Minnelide is effective against GBC cells. We have previously shown that triptolide/Minnelide reduces tumor growth in various cancer models via regulating epithelial -mesenchymal transition (EMT), an important mechanism underlying metastasis. In our preliminary findings using two GBC cell lines, GB-d1 and NOZ, we demonstrate that triptolide inhibits the proliferation of GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with Minnelide, exhibited a significant reduction in tumor weights and volume. In order to elucidate the mechanism underlying triptolide/Minnelide mediated inhibition of cellular proliferation in GBC cells and reduction in tumor growth, we identified Aurora Kinase A (AURKA) and FAK as two new targets for triptolide action in GBC cells. Triptolide regulates the activity of AURKA and FAK via an adhesion signaling protein NEDD9 which regulates the activation of several oncogenic proteins including FAK and SRC. By targeting both FAK and AURKA, triptolide disrupts the integrity of focal adhesion structures via deregulating adhesion signaling network. In addition, by targeting AURKA in GBC cells triptolide inhibits the cap-dependent translation machinery via eukaryotic translation initiation factor 4E (eIF4E). Our preliminary findings regarding potential use of Minnelide in GBC are promising. <!–EndFragment–> Citation Format: Mahendra K. Singh, Kaustav Majumder, Bhuwan Giri, Nivedita Arora, Shrey Modi, Vrishketan Sethi, Claudia P. Garcia, Juan C. Roa, Vikas Dudeja, Sulagna Banerjee, Ashok K. Saluja. Targeting adhesion signaling network blocks tumor growth in gallbladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1916.