PSMA- and SSTR-targeted imaging and tissue characteristics in woodchuck hepatocellular carcinoma: an exploratory descriptive study

Abstract Background The use of prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted radiotheranostics for hepatocellular carcinoma (HCC) requires preclinical models that reproduce the features of spontaneous tumors. Woodchucks chronically infected with woodchuck hepatitis virus (WHV) develop hepatic tumors that closely resemble hepatitis B virus-induced human HCC. We further characterized PSMA-targeted imaging and normal-tissue expression, including the salivary glands, and evaluated SSTR2/5 expression and [ 68 Ga]Ga-DOTATOC uptake. We also explored the feasibility and short-term tolerability of a single [ 177 Lu]Lu-PSMA-617 administration. Results Twelve tumor-bearing woodchucks underwent PET/CT imaging with [ 68 Ga]Ga-PSMA-11 or [ 68 Ga]Ga-DOTATOC (six animals each), with tissue expression assessed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. PSMA transcripts were detected in tumors, liver and salivary glands, and PSMA staining was present in tumor-associated microvessels and normal tissues. [ 68 Ga]Ga-PSMA-11 uptake varied within and between tumors, with a median tumor maximum standardized uptake value of 3.3 and tumor-to-liver ratio of 1.9. Uptake was also observed in salivary glands and other normal organs. Although SSTR2/5 transcripts and cytoplasmic staining were detected in tumors, only one of six animals showed strong [ 68 Ga]Ga-DOTATOC tumor uptake relative to liver. HCC was confirmed in all animals at necropsy. Tumors showed heterogeneous contrast enhancement, fibrosis and necrosis, and hepatic lymph node metastases were present in 6 of 10 animals in which lymph nodes were sampled. A single [ 177 Lu]Lu-PSMA-617 administration and serial follow-up were feasible in three animals; no changes in appetite or activity were observed. Conclusions SSTR-targeted imaging and normal-tissue characterization add to previous PSMA imaging findings in woodchuck HCC. The observed variation in tumor histopathology, target expression and radiopharmaceutical uptake supports further use of this model to study molecular imaging and radiopharmaceutical delivery in spontaneous HCC.