Oncotarget

Research Papers:

The pancreatic niche inhibits the effectiveness of sunitinib treatment of pancreatic cancer

Neus Martínez-Bosch, Pedro Enrique Guerrero, Mireia Moreno, Anabel José, Mar Iglesias, Jessica Munné-Collado, Héctor Anta, Joan Gibert, Carlos Alberto Orozco, Judith Vinaixa, Cristina Fillat, Francesc Viñals and Pilar Navarro _

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Oncotarget. 2016; 7:48265-48279. https://doi.org/10.18632/oncotarget.10199

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Abstract

Neus Martínez-Bosch1, Pedro Enrique Guerrero1, Mireia Moreno1, Anabel José2,3, Mar Iglesias4, Jessica Munné-Collado4, Héctor Anta1,5, Joan Gibert1, Carlos Alberto Orozco1, Judith Vinaixa1, Cristina Fillat2,3, Francesc Viñals6, Pilar Navarro1

1Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain

2Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Barcelona, Spain

3Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain

4Pathology Service, Hospital del Mar, Barcelona, Spain

5Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain

6Catalan Institute of Oncology-IDIBELL, Barcelona University, Barcelona, Spain

Correspondence to:

Pilar Navarro, email: [email protected]

Keywords: sunitinib, pancreatic cancer, PDA, acinar carcinoma, fibrosis

Received: January 14, 2016     Accepted: June 06, 2016     Published: June 21, 2016

ABSTRACT

Current treatments for pancreatic ductal adenocarcinoma (PDA) are ineffective, making this the 4th leading cause of cancer deaths. Sunitinib is a broad-spectrum inhibitor of tyrosine kinase receptors mostly known for its anti-angiogenic effects. We tested the therapeutic effects of sunitinib in pancreatic cancer using the Ela-myc transgenic mouse model. We showed that Ela-myc pancreatic tumors express PDGFR and VEGFR in blood vessels and epithelial cells, rendering these tumors sensitive to sunitinib by more than only its anti-angiogenic activity. However, sunitinib treatment of Ela-myc mice with either early or advanced tumor progression had no impact on either survival or tumor burden. Further histopathological characterization of these tumors did not reveal differences in necrosis, cell differentiation, angiogenesis, apoptosis or proliferation. In stark contrast, in vitro sunitinib treatment of Ela-myc– derived cell lines showed high sensitivity to the drug, with increased apoptosis and reduced proliferation. Correspondingly, subcutaneous tumors generated from these cell lines completely regressed in vivo after sunitinib treatments. These data point at the pancreatic tumor microenvironment as the most likely barrier preventing sunitinib treatment efficiency in vivo. Combined treatments with drugs that disrupt tumor fibrosis may enhance sunitinib therapeutic effectiveness in pancreatic cancer treatment.


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