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 small molecule therapeutics. The targeted depletion of hyaluronan with 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.
Highlights
Pancreatic ductal adenocarcinoma (PDA) are further distinguished by an intense fibroinflammatory infiltrate comprised of several classes of immune cell subsets, fibroblasts in various states of activation, a paucity of vessels, and a complex extracellular matrix that includes high concentrations of hyaluronan (HA), amidst a dense fibrosis
The hypoperfused state in PDA instead arises from vascular collapse of otherwise normal vessels under inordinately high interstitial gel–fluid pressures, themselves the result of the extraordinary swelling forces generated by the unusual properties of hydrated HA in entanglement with a dense collagen fibrillar network [4,17]
We previously identified significantly lower apparent diffusion coefficient (ADC) values in autochthonous KrasLSL-G12D/+ ;Trp53LSL-R172H/+ ;Cre (KPC) PDAs versus either orthotopic or subcutaneously engrafted tumors in ADC maps generated with b-values of 0, 500, and 1000 s/mm2, consistent with decreased Brownian motion and mobility of water [21]
Summary
The unusual structure of HA, together with its highly negative charge, contributes to its ability [1,2]. The unusual structure of HA, together with its highly negative charge, contributes to its ability to bind water avidly (up to 15 water molecules per disaccharide unit), resulting in an immobile to bind water avidly (up to 15 water molecules per disaccharide unit), resulting in an immobile gel–. HA is found in small amounts in virtually all organs of the body, providing fluid phase. HA is found in small amounts in virtually all organs of the body, providing turgor and turgor and helping to define tissue architecture. In PDA, interstitial HA concentrations helping to define tissue architecture. The resulting hypoperfusion and barriers to diffusion and convection serve as primary serve as primary mechanisms of resistance to systemically delivered therapies [3,4]. When combined with a conventional cytotoxic, the resulting increase in increase in intratumoral drug concentrations significantly improved objective response and overall intratumoral drug concentrations significantly improved objective response and overall survival [5]
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