TY - JOUR
T1 - Non-invasive monitoring of stromal biophysics with targeted depletion of hyaluronan in pancreatic ductal adenocarcinoma
AU - Maloney, Ezekiel
AU - Dufort, Christopher C.
AU - Provenzano, Paolo P.
AU - Farr, Navid
AU - Carlson, Markus A.
AU - Vohra, Ravneet
AU - Park, Joshua
AU - Hingorani, Sunil R.
AU - Lee, Donghoon
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
KW - Hyaluronan
KW - Magnetic resonance imaging
KW - PEGPH20
KW - Pancreatic ductal adenocarcinoma
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U2 - 10.3390/cancers11060772
DO - 10.3390/cancers11060772
M3 - Article
C2 - 31167451
AN - SCOPUS:85070675122
SN - 2072-6694
VL - 11
JO - Cancers
JF - Cancers
IS - 6
M1 - 772
ER -