Abstract
Recent advances in molecular subtyping of Pancreatic Ductal Adenocarcinoma (PDAC) support individualization of therapeutic strategies in this most aggressive disease. With the emergence of various novel therapeutic strategies and neoadjuvant approaches in this quickly deteriorating disease, robust approaches for fast evaluation of therapy response are urgently needed. To this aim, we designed a preclinical imaging-guided therapy trial where genetically engineered mice harboring endogenous aggressive PDAC were treated with the MEK targeting drug refametinib, which induces rapid and profound tumor regression in this model system. Multi-parametric non-invasive imaging was used for therapy response monitoring. A significant increase in the Diffusion-Weighted Magnetic Resonance Imaging derived Apparent Diffusion Coefficient (ADC) was noted already 24 hours after treatment onset. Histopathological analyses showed increased apoptosis and matrix remodeling at this time point. Our findings suggest the ADC parameter as an early predictor of therapy response in PDAC.
Highlights
Treatment of Pancreatic Ductal Adenocarcinoma (PDAC) is suffering from largely ineffective therapeutic regimens[1]
DW-Magnetic Resonance Imaging (MRI) has been evaluated for PDAC staging[16], differentiation of pancreatitis from PDAC17, tumor identification in high risk individuals[18] and as therapy response parameter[19,20]
Animals were weekly scanned and once the tumor reached the size of 200 mm[3] or bigger, animals were enrolled into the study. (b) Exemplary presentation of Positron Emission Tomography (PET) analysis: T2w and corresponding PET images before and after the therapy demonstrating presence of two tumors with different [18F]-FDG uptake in the same animal
Summary
Treatment of Pancreatic Ductal Adenocarcinoma (PDAC) is suffering from largely ineffective therapeutic regimens[1]. Advancements in our understanding of PDAC and subtyping of cancers potentially amendable to differential treatment strategies emphasizes the importance of individualized approaches and early evaluation of therapy effectiveness[4,5]. Therapy-induced morphological or cellular changes that are potentially relevant in neoadjuvant settings cannot be detected by structural imaging such as CT or T1-/T2-weighted-Magnetic Resonance Imaging (MRI). These limitations clearly necessitate better imaging based markers for therapy response. DW-MRI has been evaluated for PDAC staging[16], differentiation of pancreatitis from PDAC17, tumor identification in high risk individuals[18] and as therapy response parameter[19,20]
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