AUM001 potentiates the anti-tumor activity of gemcitabine in an AsPC-1 PDAC model

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with extremely poor survival outcomes and limited therapeutic options. The proliferative and metastatic nature of PDAC has been attributed to dysregulated mRNA translation of pro-tumorigenic genes and mitogen activating protein kinase interacting kinase (MNK) proteins are known to act as regulatory switches for initiation of oncogenic mRNA translation via MNK-coupled phosphorylation of eukaryotic translation factor 4E (eIF4E). Previously, it was demonstrated that in vitro pharmacological inhibition of MNK proteins may act synergistically with gemcitabine (GEM) to enhance the latter’s cytostatic effect and promote apoptosis. AUM001 is a novel MNK1/MNK2 inhibitor undergoing clinical trials in various solid tumors. We hypothesize that combination of AUM001 with GEM would have synergistic effect in moderating the tumor growth kinetics.

Human PDAC cells AsPC-1 were subcutaneously implanted into BALB/c nude mice and randomized into four treatment groups once tumor volume of 100mm3 was reached. Saline (control) and GEM were administered intraperitoneal biweekly while AUM001 was given oral on daily basis for four weeks. The combination of GEM and AUM001 was administered at similar doses and frequency. Body weight and tumor volume were measured thrice weekly. Immunohistochemistry staining was performed on formalin-fixed paraffin-embedded tissue sections for proliferation, angiogenesis and stromal markers. Statistical analysis with non-parametric methods was used. P values < 0.05 were considered statistically significant.

The combination of GEM and AUM001 (GA) was found to be tolerable with minimal loss of 6.4% in body weight from start of treatment. Marked decline by 25% in relative tumor volume was observed in GA group versus control mice (P=0.016). Addition of AUM001 led to a lower extent of phosphorylation of EIF4E. It was notable that the spatial compactness of CCND1 and Ki67-positive cells in the tumor was greatly reduced in GEM and GA groups than control and AUM001. Apoptotic marker CC3 was significantly higher in GEM and GA groups (P 0.05). Tumor microvessel density marker CD31 was lesser with the GA group, compared to single agent GEM- and AUM001-treated groups (P=0.032).

This study demonstrated that the addition of AUM001 to standard chemotherapy GEM is well-tolerated and confers a greater anti-tumor effect than single agent GEM. Pharmacodynamic analysis suggests that AUM001 may potentiate the reduction in pro-tumorigenic protein expression and slow the tumor growth kinetics. This is the first study depicting clinical activity of AUM001 in combination with chemotherapy for the treatment of PDAC. Future studies evaluating the combination of AUM001 and GEM are clearly warranted to confirm these findings.

Balram Chowbay.

Agency for Science, Technology & Research; Singapore Economic Development Board; Enterprise SIngapore; NAtional Research Foundation.

All authors have declared no conflicts of interest.