Abstract LB-230: Nanotherapy targeting metastatic factor RHAMMB-positive pancreatic neuroendocrine tumors

Abstract

Abstract Pancreatic neuroendocrine tumors (PNETs) represent one-third of gastroenteropancreatic neuroendocrine tumors and are the second malignancy of the pancreas. The 5-year survival rate of metastatic PNETs is only about 15%. We have recently demonstrated that receptor for hyaluronic acid-mediated motility isoform B (RHAMMB) is upregulated in PNETs and promotes metastasis of PNETs. We have also reported that Bcl-xL accelerates the formation of PNETs with invasive properties. Here, we propose a RHAMM-targeted combination therapy (RCT), as a novel treatment for PNETs. RCT is designed to accomplish a synergistic apoptotic/anticancer effect, by aiming RHAMMB, a receptor for hyaluronic acid (HA), and codelivering Bcl-xL siRNA with mitochondria-fusing peptide to kill PNET cells. Yet, it is a substantial challenge to codeliver multiple drugs to RHAMM-expressing tumors. To simultaneously transport these unconventional therapeutics for a synergistic effect, a siRNA for Bcl-xL and a mitochondria-fusing peptide are layered onto a nanocore by charge-charge interaction, followed by a layer of HA for targeting RHAMMB. We showed that the prepared RCT is efficiently internalized by RHAMMB-positive cells, but not by RHAMMB-negative cells. We have found that the encapsulated Bcl-xL siRNA and the mitochondria-fusing peptide are released inside cells to silence Bcl-xL gene expression and induce apoptosis by fusing the mitochondrial membrane. A synergistic cell killing effect was achieved in vitro (> 83% cell death). In a preclinical mouse model, we demonstrated that systemically-injected RCT significantly reduced tumor burden (> 65% reduction) and sustained the blood glucose levels of mice bearing RHAMMB-positive PNETs. Together, the developed RCT can serve as a promising drug delivery system for RHAMMB-overexpressed cancer treatments. Citation Format: Seung Koo Lee, Xiang Chen, Yi-Chieh Nancy Du, Ching-Hsuan Tung. Nanotherapy targeting metastatic factor RHAMMB-positive pancreatic neuroendocrine tumors [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 LB-230.