Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy

Jun Zhao, Huamin Wang, Cheng Hui Hsiao, Diana S.L. Chow, Eugene J. Koay, Yaan Kang, Xiaoxia Wen, Qian Huang, Ying Ma, James A. Bankson, Stephen E. Ullrich, Willem Overwijk, Anirban Maitra, David Piwnica-Worms, Jason B. Fleming, Chun Li

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It has an excessive desmoplastic stroma that can limit the intratumoral delivery of chemotherapy drugs, and protect tumor cells against radiotherapy. Therefore, both stromal and tumor compartments need to be addressed in order to effectively treat PDAC. We hereby co-deliver a sonic hedgehog inhibitor, cyclopamine (CPA), and a cytotoxic chemotherapy drug paclitaxel (PTX) with a polymeric micelle formulation (M-CPA/PTX). CPA can deplete the stroma-producing cancer-associated fibroblasts (CAFs), while PTX can inhibit tumor proliferation. Here we show that in clinically relevant PDAC models, M-CPA effectively modulates stroma by increasing microvessel density, alleviating hypoxia, reducing matrix stiffness while maintaining the tumor-restraining function of extracellular matrix. M-CPA/PTX also significantly extends animal survival by suppressing tumor growth and lowering the percentages of poorly to moderately differentiated tumor phenotypes. Our study suggests that using multifunctional nanoparticles to simultaneously target stromal and tumor compartments is a promising strategy for PDAC therapy.

Original languageEnglish (US)
Pages (from-to)215-228
Number of pages14
JournalBiomaterials
Volume159
DOIs
StatePublished - Mar 2018
Externally publishedYes

Keywords

  • Cancer-associated fibroblast
  • Pancreatic cancer
  • Polymeric micelles
  • Sonic hedgehog signaling
  • Stromal modulation
  • Paclitaxel/chemistry
  • Signal Transduction/drug effects
  • Polymers/chemistry
  • Animals
  • Mice, Nude
  • Micelles
  • Female
  • Mice
  • Cell Proliferation/drug effects
  • Pancreatic Neoplasms/drug therapy

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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