Pancreatic cancer (PC) is a highly aggressive disease that is poorly responsive to available immunotherapy approaches, such as checkpoint inhibitors. Post-translational protein modification (PTM) by small ubiquitin-like modifier (SUMO) is upregulated in cancer, and high expression of SUMOylation-related factors correlates with poor survival in PC. TAK-981 is a novel inhibitor of SUMOylation that has demonstrated induction of anti-tumor immune responses in preclinical models. Our hypothesis is that TAK-981 will decrease SUMOylated proteins and subsequently modulate the tumor microenvironment to increase anti-tumor immunity.

In order to recapitulate the microenvironment of human PC, a 3-dimensional organoid cell line derived from a genetically-engineered “KPC” mouse was used. Organoids were injected orthotopically into the head of the pancreas via laparotomy. Once tumors reached 5-7 mm in diameter on ultrasound imaging, mice were randomized to one of two treatment groups: Control/Vehicle versus TAK-981 (15mg/kg) delivered daily via intraperitoneal injection. Tumors were harvested on day 14 for gene expression analysis by quantitative real time PCR (RT-qPCR).

Tumor growth (Fig. 1) in the TAK-981 15mg/KG daily group (mean + SD volume = 207 + 109 mm3) was significantly inhibited compared to the vehicle group (595 + 141 mm3, p < 0.01). Immunohistochemical staining for CD 31 (Fig. 2) and Caspase 3 indicated a reduction of angiogenesis and increased apoptosis of tumor cells, consistent with the well-established roles of SUMOylation in angiogenesis and tumorigenesis. Gene expression analysis of tumor lysates showed a 26-fold increase in expression of Interferon beta (p<0.05), and an almost 2-fold increase in expression of genes related to dendritic cell activation, including CD80 (p<0.05) and CD86 (p=0.14) in the TAK-981 group, suggesting a modulation of the immune microenvironment.

Our results suggest that the inhibition of SUMOylation with TAK-981 is associated with improved local tumor control and changes in the immunosuppressive tumor microenvironment. We expect that TAK-981 will improve PC responsiveness to immunotherapy, such as with checkpoint inhibitors.