1. Academic Validation
  2. Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models

Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models

  • Sci Rep. 2020 Feb 19;10(1):2935. doi: 10.1038/s41598-020-59893-5.
Eunji Hong 1 2 Sujin Park 3 Akira Ooshima 1 Chang Pyo Hong 4 Jinah Park 1 Jin Sun Heo 1 Siyoung Lee 1 Haein An 1 Jin Muk Kang 1 Seok Hee Park 2 Joon Oh Park 5 Seong-Jin Kim 1 6 4 7
Affiliations

Affiliations

  • 1 Precision Medicine Research Center, Advanced Institute of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do, 16229, Republic of Korea.
  • 2 Department of Biological Science, Sungkyunkwan University, Suwon, 16419, Gyeonggi-do, Republic of Korea.
  • 3 Precision Medicine Research Center, Advanced Institute of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do, 16229, Republic of Korea. sujinp@snu.ac.kr.
  • 4 TheragenEtex Bio Institute, Suwon, Gyeonggi-do, 16229, Republic of Korea.
  • 5 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • 6 Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Gyeonggi-do, 16229, Republic of Korea.
  • 7 Medpacto Inc., Seoul, Republic of Korea.
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies. TGF-β is strongly expressed in both the epithelial and stromal compartments of PDAC, and dysregulation of TGF-β signalling is a frequent molecular disturbance in PDAC progression and metastasis. In this study, we investigated whether blockade of TGF-β signalling synergizes with nal-IRI/5-FU/LV, a chemotherapy regimen for malignant pancreatic Cancer, in an orthotopic pancreatic tumour mouse model. Compared to nal-IRI/5-FU/LV treatment, combining nal-IRI/5-FU/LV with vactosertib, a TGF-β signalling inhibitor, significantly improved long-term survival rates and effectively suppressed invasion to surrounding tissues. Through RNA-sequencing analysis, we identified that the combination treatment results in robust abrogation of tumour-promoting gene signatures and positive enrichment of tumour-suppressing and apoptotic gene signatures. Particularly, the expression of tumour-suppressing gene Ccdc80 was induced by vactosertib and further induced by vactosertib in combination with nal-IRI/5-FU/LV. Ectopic expression of CCDC80 suppressed migration and colony formation concomitant with decreased expression of epithelial-to-mesenchymal transition (EMT) markers in pancreatic Cancer cells. Collectively, these results indicate that combination treatment of vactosertib with nal-IRI/5-FU/LV improves overall survival rates in a mouse model of pancreatic Cancer by suppressing invasion through CCDC80. Therefore, combination therapy of nal-IRI/5-FU/LV with vactosertib could provide clinical benefits to pancreatic Cancer patients.

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