Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer

Niranjan Awasthi, Stefan Hinz, Rolf A. Brekken, Margaret A. Schwarz, Roderich E. Schwarz

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma (PDAC) therapy. VEGF, PDGF, FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC. Nintedanib is a triple angiokinase inhibitor that targets VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β signaling. We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC. Nintedanib inhibited proliferation of cells from multiple lineages found in PDAC, with gemcitabine enhancing inhibitory effects. Nintedanib blocked PI3K/MAPK activity and induced apoptosis in vitro and in vivo. In a heterotopic model, net local tumor growth compared to controls (100%) was 60.8 ± 10.5% in the gemcitabine group, -2.1 ± 9.9% after nintedanib therapy and -12.4 ± 16% after gemcitabine plus nintedanib therapy. Effects of therapy on intratumoral proliferation, microvessel density and apoptosis corresponded with tumor growth inhibition data. In a PDAC survival model, median animal survival after gemcitabine, nintedanib and gemcitabine plus nintedanib was 25, 31 and 38 days, respectively, compared to 16 days in controls. The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib-controlled mechanisms as targets for improved clinical PDAC therapy.

Original languageEnglish (US)
Pages (from-to)59-66
Number of pages8
JournalCancer Letters
Volume358
Issue number1
DOIs
StatePublished - Mar 1 2015

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gemcitabine
Pancreatic Neoplasms
Adenocarcinoma
Therapeutics
nintedanib
Apoptosis
Fibroblast Growth Factor Receptors
Cytotoxins
Cell Lineage
Growth
Microvessels
Phosphatidylinositol 3-Kinases
Vascular Endothelial Growth Factor A
Neoplasms

Keywords

  • Angiogenesis
  • Chemotherapy
  • Combination therapy
  • Nintedanib
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer. / Awasthi, Niranjan; Hinz, Stefan; Brekken, Rolf A.; Schwarz, Margaret A.; Schwarz, Roderich E.

In: Cancer Letters, Vol. 358, No. 1, 01.03.2015, p. 59-66.

Research output: Contribution to journalArticle

Awasthi, Niranjan ; Hinz, Stefan ; Brekken, Rolf A. ; Schwarz, Margaret A. ; Schwarz, Roderich E. / Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer. In: Cancer Letters. 2015 ; Vol. 358, No. 1. pp. 59-66.
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