Abstract 2902: Beneficial effect of vactosertib combined with nal-IRI5-FU/LV in pancreatic cancer treatment

Pancreatic cancer is one of leading causes of cancer-related mortality in the world. Treatment of pancreatic cancer is difficult due to aggressiveness, distal metastasis, and genetic and epigenetic alterations. Especially, TGF-β is highly expressed in the pancreatic cancer patients, and it leads aggressive tumor metastasis. Regulation of TGF-β signaling is essential for controlling tumor progression and metastasis because TGF-β is involved in cell proliferation, epithelial-to-mesenchymal transition, angiogenesis, metastasis, and immune responses in cancer. Therefore, inhibition of TGF-β signaling may be the key concept of effective chemotherapies for metastatic pancreatic cancer. Recently, nanoliposomal iriotecan (nal-IRI), 5-flourouracil (5-FU) and leucovorin (LV) adjuvant therapy has been applied for pancreatic cancer patients9 treatment. Vactosertib, one of the leading TGF-β inhibitor, has been used for clinical trials in many chemotherapy strategies. In this study, we investigated the combination treatment effect of nal-IRI/5-FU/LV and vactosertib on pancreatic cancer in syngeneic orthotopic pancreatic mouse model. The combination treatment significantly increased survival rate compare with control or single treatment of vactosertib or nal-IRI/5-FU/LV. In the histological analysis showed that cancer cell invasion to surrounding tissues was markedly reduced in vactosertib and combination treatment groups. In the RNA-sequencing analysis of tumor RNA, the apoptotic process are positively regulated in vactosertib plus nal-IRI/5-FU/LV group. Furthermore, we found the up-regulated differentially expressed gene (DEG), CCDC80, involved in cell migration, invasion and apoptosis. We ectopically overexpressed CCDC80 on pancreatic cancer cell lines and demonstrated the tumor suppressive role of CCDC80. In conclusion, the combination treatment with vactosertib with nal-IRI/5-FU/LV improved pancreatic cancer survival by inhibiting tumor invasion and inducing apoptosis. These results indicate that combination therapy can be applied to clinical trials in pancreatic cancer patient. This study supported by KHIDI grant (HI14C2640) and National RD 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2902.