P3.01-043 Inhibition of Ornithine Decarboxylase Facilitates Pegylated Arginase Treatment in Lung Adenocarcinoma Xenograft Models: Topic: Functional Biology in Lung Cancer

Abstract

Arginine depletion has shown promising anticancer effects among arginine auxotrophic cancers that are deficient in argininosuccinate synthetase (ASS) and/or ornithine transcarbamylase (OTC). Pegylated arginase (PEG-BCT-100 (rhArg1peg5000)) works as an arginine depletor by converting arginine to ornithine. However, accumulated ornithine can be channeled via ornithine decarboxylase (ODC) to produce polyamines that are known to promote tumor growth. We postulate that ODC inhibition could rescue anticancer effects of BCT-100 in lung adenocarcinoma. A panel of 7 lung adenocarcinoma cell lines (H23, H358, HCC827, H1650, H1975, HCC2935 and HCC4006) was used to study the in vitro effect of BCT-100 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The in vivo effect of BCT-100 was studied using 5 nude mice xenograft models lines (H358, HCC827, H1650, H1975 and HCC4006). Protein expression and arginine concentration were investigated by Western blot and ELISA respectively. TUNEL assay was performed to identify apoptosis. BCT-100 reduced in vitro cell viability across different cell lines. However, BCT-100 could only suppress tumor growth in HCC4006 xenograft model, while paradoxical growth stimulation was observed in H358, HCC827, H1650 and H1975 xenograft models. Upon BCT-100 treatment, ODC was induced in two solid tumor xenograft models (H1650 and H1975), while unaltered in cystic tumor xenograft models (H358 and HCC827) and the remaining solid tumor (HCC4006) xenograft model. In both H1650 and H1975 xenografts, combined BCT-100 and α-Difluoromethylornithine (DFMO, an ODC inhibitor) significantly suppressed tumor growth compared with control or single arm treatments with median survival doubled compared with control group. Apoptosis was activated in combination arm in both xenograft models. In HCC4006 xenograft model, the tumor suppression effect of BCT-100 arm and DFMO/BCT-100 arm was similar. Apoptosis was noted in DFMO, BCT-100 and DFMO/BCT arms. Inhibition of ODC by DFMO is essential in BCT-100 (pegylated arginase) treatment in lung adenocarcinoma.