Targeting and Modulation of the Tumor Stroma in Pancreatic Cancer

J. Schnittert

Research output: ThesisPhD Thesis - Research UT, graduation UT

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the cancer type with the worst prognosis. The 1-year survival rate is 20%, whereas the 5-year survival rate is 8%. A surgical resection is only feasible in a small percentage of PDAC tumors, making radiotherapy or cytotoxic chemotherapy the golden standard treatment. The pancreatic tumor stroma has shown to strongly support tumor growth and metastasis of PDAC. Human pancreatic stellate cells (hPSCs), as precursors of cancer-associated fibroblast-like myofibroblasts (CAF), are the main component of the tumor stroma of pancreatic ductal adenocarcinoma (PDAC). Upon activation, human hPSCs differentiate into CAF and promote tumor growth, invasion, and metastasis in PDAC.
In this thesis, we focused on finding therapeutic strategies to inhibit the tumor-promoting functions of activated hPSCs and thereby modulate the tumor stroma in pancreatic cancer. We identified new therapeutic agents, including microRNA-199a, and the bioactive lipid lipoxin A4, which are capable to reprogram activated hPSCs into their quiescent phenotype. Since microRNAs are not stable by themselves we designed a microRNA delivery system for their specific delivery to CAFs. Additionally, we found the therapeutic target integrin alpha 11 to control differentiation of hPSCs into activated hPSCs and be specifically expressed on CAFs within the stroma of PDAC. This makes integrin alpha 11 a highly suitable target for drug delivery applications. Therefore we designed an integrin alpha 11 specific peptide for targeting of drug delivery systems to activated hPSCs in the stroma of PDAC.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Twente
Supervisors/Advisors
  • Storm, G., Supervisor
  • Prakash, J. , Co-Supervisor
Award date6 Jul 2018
Place of PublicationEnschede
Publisher
Print ISBNs978-90-365-4585-3
Electronic ISBNs978-90-365-4585-3
DOIs
Publication statusPublished - 6 Jul 2018

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