Abstract 5253: MEK-ERK pathway inhibition reduces mucin production in a murine xenograft model of pseudomyxoma peritonei

Abstract

Abstract Introduction: Pseudomyxoma peritonei (PMP) is characterized by compressive organ dysfunction from progressive intra-peritoneal accumulation of mucinous ascites. MUC2 is the primary secreted mucin in PMP and the MAPK signaling pathway is involved in MUC2 promoter regulation. We hypothesized that targeted inhibition of the MAPK pathway using small molecule drugs would be a novel, effective and safe therapeutic strategy in this malignancy by reducing mucinous tumor burden. Methods: The therapeutic effect of RDEA119 (BAY 86-9766), a specific MEK 1/2 inhibitor, was assessed in mucin-secreting human colon cancer LS174T cells in vitro and murine xenograft models of LS174T and human appendiceal PMP in vivo, by serial parametric measurements, MUC2 transcripts via real time RT-PCR and MUC2 protein expression via immunofluorescence assays. Results: MUC2 mRNA accounted for approximately 98% of the overall message encoding for secreted gel-forming mucins, with a relatively small contribution from other known gel-forming mucins (MUC5AC, MUC5B, MUC6 and MUC19) in LS174T cells and in the murine xenograft models. RDEA119 significantly inhibited basal MUC2 mRNA levels (DMEM: 0.02 ± 0.0007 vs. RDEA119 5x10−6M: 0.007 ± 0.0003; 48 hr; p<0.0001) and sodium butyrate-stimulated MUC2 mRNA levels (NaB 2.5 mM: 0.06 ± 0.004 vs. RDEA119 5x10−6M + NaB 2.5 mM: 0.004 ± 0.0001; 48 hr; p<0.0001) in LS174T cells at 48 hours. In the subcutaneous LS174T murine xenograft model, chronic oral therapy with RDEA119 inhibited mucinous tumor growth (Day 28: PBS-PO: 3159 ± 1019 mm3 vs. RDEA119-PO: 1024 ± 417 mm3; p=0.04), which translated into a significant improvement in median overall survival (PBS-PO: 17.5 days vs. RDEA119-PO: > 43 days; p=0.02). In the intra-peritoneal PMP murine xenograft model treated with chronic oral RDEA119, MUC2 protein analysis by immunofluorescence demonstrated non-significant gross reduction in MUC2 protein volume (PBS-PO: 41695993 ± 13154727 µm2 vs. RDEA-PO: 35447861 ± 6079224 µm2; p>0.05) and tumor cell count (PBS-PO: 79889 ± 25654 cells vs. RDEA-PO: 52093 ± 15433 cells; p>0.05), suggesting a dual inhibitory effect of RDEA119 on mucin production and tumor cell proliferation. Conclusions: MEK-ERK pathway inhibitor RDEA119 demonstrated effective inhibition of MUC2 production in vitro and in vivo and improved survival in a subcutaneous murine xenograft model of PMP. Reduced mucinous tumor burden by targeted inhibition of the MAPK pathway may be a novel and effective strategy to reduce tumor-specific symptoms, improve overall survival and reduce the need for morbid cytoreductive surgical procedures in patients with recurrent PMP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5253. doi:1538-7445.AM2012-5253