Evaluation of Diffusion-weighted magnetic resonance imaging for therapy response in pancreatic cancer in mouse models

Introduction:

New therapeutic regimens for otherwise lethal pancreatic ductal adenocarcinoma (PDAC) are rapidly emerging. Thus, imaging-based biomarkers that would allow early assessment of therapy response would be of great need.

Methods:

In a preclinical therapy approach, we used a a Ptf1awt/cre;Kraswt/LSL-KrasG12D;p53fl/fl (CKP furtheron) genetically engineered mouse model (GEMM) that develops moderately differentiated PDAC with strong stromal reaction and thus faithfully recapitulates characteristics of locally advanced human PDAC. Animals were subjected to 2 different therapy regimens, gemcitabine and refametinib, a novel MEK kinase inhibitor, and response to therapy was monitored with [18F]-fluordeoxyglucose-positron emission tomography ([18F]-FDG-PET) and T2-weighted (T2w-) and diffusion weighted-magnetic resonance imaging (DW-MRI).

Results:

T2w-MRI allowed estimations of tumor volume changes. Targeted MEK inhibition by refametinib induced a prolongation of animal life and strong reduction in tumor volume as early as 5 days upon therapy onset, while gemcitabine treatment did not induce dramatic changes both in survival nor tumor volume. DW-MRI derived apparent diffusion coefficient (ADC) parameter was used to estimate changes in tissue composition. Refametinib treatment induced a reorganization of tumor stroma that could be detected as an increase in ADC values as early as 24h after therapy onset (pre-therapy: 0,973 ± 0,095µm2/s*1000 post-therapy: 1,107 ± 0,098µm2/s*1000) while ADC did not change in the gemcitabine treated group (pre-therapy: 1,009 ± 0,080µm2/s*1000; post-therapy: 1,026 ± 0,113µm2/s*1000). We further evaluated DW-MRI in patients with stage IV PDAC that received first line chemotherapy and observed concomitant changes in tumor volume and ADC.

Conclusions:

Our results warrant further evaluation of thisADC parameter for early response evaluation in PDAC.