Non-invasive monitoring of stromal biophysics with targeted depletion of hyaluronan in pancreatic ductal adenocarcinoma

Ezekiel Maloney, Christopher C. Dufort, Paolo P. Provenzano, Navid Farr, Markus A. Carlson, Ravneet Vohra, Joshua Park, Sunil R. Hingorani, Donghoon Lee

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by a pronounced fibroinflammatory stromal reaction consisting of inordinate levels of hyaluronan (HA), collagen, immune cells, and activated fibroblasts that work in concert to generate a robust physical barrier to the perfusion and diffusion of smallmolecule therapeutics. The targeted depletion of hyaluronanwith a PEGylated recombinant human hyaluronidase (PEGPH20) lowers interstitial gel–fluid pressures and re-expands collapsed intratumoral vasculature, improving the delivery of concurrently administered agents. Here we report a non-invasive means of assessing biophysical responses to stromal intervention with quantitative multiparametric magnetic resonance imaging (MRI) at 14 Tesla (T).We found that spin-spin relaxation time T2 values and glycosaminoglycan chemical exchange saturation transfer (GagCEST) values decreased at 24 h, reflecting depletion of intratumoral HA content, and that these parameters recovered at 7 days concurrent with replenishment of intratumoral HA. This was also reflected in an increase in low-b apparent diffusion coefficient (ADC) at 24 h, consistent with improved tumor perfusion that again normalized at 7 days after treatment. Phantom imaging suggests that the GagCEST signal is driven by changes in HA versus other glycosaminoglycans. Thus, multiparametric magnetic resonance imaging (MRI) can be used as a non-invasive tool to assess therapeutic responses to targeted stromal therapy in PDA and likely other stroma-rich solid tumors that have high levels of hyaluronan and collagen.

Original languageEnglish (US)
Article number772
JournalCancers
Volume11
Issue number6
DOIs
StatePublished - Jun 2019

Bibliographical note

Funding Information:
Funding: This research was funded by grants from the NIH/National Cancer Institute (R01CA188654—D.L., R01CA161112—S.R.H., R01CA181385—P.P.P.), as well as the Giles W. and Elise G. Mead Foundation (S.R.H.). This research was also supported by the Small Animal Imaging Shared Resource of the Fred Hutch/University of Washington Cancer Consortium (P30CA015704). E.M. is supported in part through a National Institutes of Health (NIH), National Research Service Award training grant held by the University of Washington Gastroenterology Division (5 T32 DK007742).

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Hyaluronan
  • Magnetic resonance imaging
  • PEGPH20
  • Pancreatic ductal adenocarcinoma

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