Functional biomarkers derived from computed tomography and magnetic resonance imaging differentiate PDAC subgroups and reveal gemcitabine-induced hypo-vascularization.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a molecularly heterogeneous tumor entity with no clinically established imaging biomarkers. We hypothesize that tumor morphology and physiology, including vascularity and perfusion, show variations that can be detected by differences in contrast agent (CA) accumulation measured non-invasively. This work seeks to establish imaging biomarkers for tumor stratification and therapy response monitoring in PDAC, based on this hypothesis. Regional CA accumulation in PDAC was correlated with tumor vascularization, stroma content, and tumor cellularity in murine and human subjects. Changes in CA distribution in response to gemcitabine (GEM) were monitored longitudinally with computed tomography (CT) Hounsfield Units ratio (HUr) of tumor to the aorta or with magnetic resonance imaging (MRI) ΔR₁ area under the curve at 60 s tumor-to-muscle ratio (AUC60r). Tissue analyses were performed on co-registered samples, including endothelial cell proliferation and cisplatin tissue deposition as a surrogate of chemotherapy delivery. Tumor cell poor, stroma-rich regions exhibited high CA accumulation both in human (meanHUr 0.64 vs. 0.34, p < 0.001) and mouse PDAC (meanAUC60r 2.0 vs. 1.1, p < 0.001). Compared to the baseline, in vivo CA accumulation decreased specifically in response to GEM treatment in a subset of human (HUr -18%) and mouse (AUC60r -36%) tumors. Ex vivo analyses of mPDAC showed reduced cisplatin delivery (GEM: 0.92 ± 0.5 mg/g, vs. vehicle: 3.1 ± 1.5 mg/g, p = 0.004) and diminished endothelial cell proliferation (GEM: 22.3% vs. vehicle: 30.9%, p = 0.002) upon GEM administration. In PDAC, CA accumulation, which is related to tumor vascularization and perfusion, inversely correlates with tumor cellularity. The standard of care GEM treatment results in decreased CA accumulation, which impedes drug delivery. Further investigation is warranted into potentially detrimental effects of GEM in combinatorial therapy regimens.