Preclinical studies in oncology are often performed in subcutaneous tumor models, where therapy success is validated by measuring changes in tumor size. We first characterized subcutaneous (sc) versus orthotopically grown neuroendocrine tumors of the pancreas (NET) with high versus low somatostatin receptor subtype 2 (SSTR2) by multimodal imaging and validated the apparent diffusion coefficient (ADC) as a potential biomarker for early therapy response following SSTR2-specific PRRT.
NET cells (native, SSTR2-transfected BON) were inoculated sc or orthotopically (n = 20) in SCID mice. Tumor characteristics were monitored using a small animal nanoScanPET/MRI: (T1/T2w anatomy, diffusion-weighted imaging, dynamic contrast-enhanced MRI, angiography; PET: Ga-68-DOTATOC, F-18-FDG. PRRT: ADC values and tumor growth were measured to monitor PRRT effects following Lu-177-DOTATOC injection.
Native BON tumors showed different morphologic and metabolic patterns between sc and orthotopic tumors. Sc BON/SSTR2 tumors were similar to native sc BON tumors, while orthotopic BON/SSTR2 tumors were strongly growth delayed and developed necrosis at an early stage compared to native orthotopic BON tumors. Accept of the orthotopic BON/SSTR2 tumors, small tumors appeared solid with high FDG uptake. During tumor growth necrosis increased and FDG decreased. Perfusion was increased in orthotopic versus sc tumors (ktrans = 0,49 min−1 and 0,31 min−1). Interestingly, Lu-177-DOTATOC uptake was ∼4 times higher in sc than in orthotopic BON/SSTR2 tumors. While the ADC reflected the early effects of PRRT (first 9 days) precisely in orthotopic tumors, therapy response could not be validated by ADC in sc tumors due to initial high liquid content in the tissue.
Successful therapy validation presupposes precise knowledge about the used xenograft und the tumor morphology in order to allow correct interpretation of therapeutic effects. In particular, the orthotopic SSTR2- tumors do reflect the physiological situation better than sc tumors and allow to use the ADC as a potential biomarker for early validation of PRRT effects.
Clinical trial identification
Legal entity responsible for the study
DKTK German Cancer Konsortium/DKFZ German Cancer Research Center
DKTK - German Cancer Konsortium, German Cancer Center (DKFZ)
All authors have declared no conflicts of interest.