Exploring currently available fibroblast activation protein targeting molecules in adrenocortical carcinoma: Navigating theranostic pathways.

Introduction: Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein (FAP) in the adrenocortical carcinoma (ACC) microenvironment may be used as potential therapeutic targets. This study investigated the diagnostic potential of four FAPi derivatives i.e. DOTA-FAPi-46 (FAPi46), DOTA.SA.FAPi (SA.FAPi), DATASA.FAPi (DATA.FAPi) and DATAC4.FAPi (C4.FAPi) and compared with standard-of-care F-FDG (FDG) in ACC.

Methods: Thirty histopathological proven cases of localized or metastatic ACC were recruited for both FDG and FAPi PET (number of patients (n) = 5 for SA.FAPi, n = 5 for DATA.FAPi, n = 5 for C4.FAPi and n = 15 for FAPi46). For biodistribution, standardized uptake values (SUV's) were computed by delineating region-of-interest on various body organs. For comparative analysis in disease identification, lesion tracer uptake was quantified using standardized uptake values corrected for lean body mass (SUL), tumor-to-background ratio (TBR), total lesion glycolysis (TLG for FDG) and total lesion FAP expression (TLF for FAPi).

Results: In overall analysis, both FAPi and FDG PET exhibited comparable mean SUL [FAPi 4.3 (8.0-1.7) vs FDG 3.9 (8.1-2.5), p-0.271], mean SUL [2.2 (4.3-1.2) vs 2.2 (3.4-1.3), p-0.897] and mean TBR [1.8 (3.2-1.2) vs 1.9 (2.7-1.2), p-0.696]. In volumetric analysis, comparable mean TLF and mean TLG was noted for the cohort [9.3 (53.7-4.5) vs 11.8 (33.0-4.3), p-0.107]. Sub-categorical analysis demonstrated complete concordant findings for both radiotracers in detection of all primary lesions, nodal lesions and distant metastases in lung and peritoneum with discordant findings in liver (22%) and skeletal lesions (33%). For lesion detection, DATA.FAPi and FAPi46 showed 100% concordance with FDG scan findings in metastatic disease. SA.FAPi exhibited 33% discordance by detecting an additional skeletal lesion, while C4.FAPi had 10% discordance, missing one liver lesion identified by FDG. Three  Ga-FAP derivatives (SA.FAPi, DATA.FAPi, and C4.FAPi) exhibited similar biodistribution, with uptake in the salivary glands, thyroid, liver, pancreas, muscles, and kidneys, and variable uptake in the lacrimal glands, extra-ocular muscles, oral mucosa, and uterus. In contrast, FAPi46 physiological expression was noted in salivary glands and muscles, with no uptake in other organs. Pancreatic uptake was highest for SA.FAPi (SUVmean 11.8), DATA.FAPi (12.1), and C4.FAPi (10.8), while FAPi46 had the lowest (1.7). Conversely, FAPi46 exhibited the highest muscle uptake (SUVmean 4.3) compared to SA.FAPi (1.7), DATA.FAPi (1.4), and C4.FAPi (1.0).

Conclusion: All the existing FAP inhibitor molecules were comparable to FDG PET for mapping disease spread and appeared as potential theranostic targets for the management of ACC.