TY - JOUR
T1 - TSPO-targeted PET and optical probes for the detection and localization of premalignant and malignant pancreatic lesions
AU - Cohen, Allison S.
AU - Li, Jun
AU - Hight, Matthew R.
AU - McKinley, Eliot
AU - Fu, Allie
AU - Payne, Adria
AU - Liu, Yang
AU - Zhang, Dawei
AU - Xie, Qing
AU - Bai, Mingfeng
AU - Ayers, Gregory D.
AU - Tantawy, Mohammed Noor
AU - Smith, Jarrod A.
AU - Revetta, Frank
AU - Kay Washington, M.
AU - Shi, Chanjuan
AU - Merchant, Nipun
AU - Charles Manning, H.
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/11/15
Y1 - 2020/11/15
N2 - Purpose: Pancreatic cancer is among the most aggressive malignancies and is rarely discovered early. However, pancreatic “incidentalomas,” particularly cysts, are frequently identified in asymptomatic patients through anatomic imaging for unrelated causes. Accurate determination of the malignant potential of cystic lesions could lead to life-saving surgery or spare patients with indolent disease undue risk. Current risk assessment of pancreatic cysts requires invasive sampling, with attendant morbidity and sampling errors. Here, we sought to identify imaging biomarkers of high-risk pancreatic cancer precursor lesions. Experimental Design: Translocator protein (TSPO) expression, which is associated with cholesterol metabolism, was evaluated in premalignant and pancreatic cancer lesions from human and genetically engineered mouse (GEM) tissues. In vivo imaging was performed with [18F]V-1008, a TSPO-targeted PET agent, in two GEM models. For image-guided surgery (IGS), V-1520, a TSPO ligand for near-IR optical imaging based upon the V-1008 pharmacophore, was developed and evaluated. Results: TSPO was highly expressed in human and murine pancreatic cancer. Notably, TSPO expression was associated with high-grade, premalignant intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanIN) lesions. In GEM models, [18F]V-1008 exhibited robust uptake in early pancreatic cancer, detectable by PET. Furthermore, V-1520 localized to premalignant pancreatic lesions and advanced tumors enabling real-time IGS. Conclusions: We anticipate that combined TSPO PET/IGS represents a translational approach for precision pancreatic cancer care through discrimination of high-risk indeterminate lesions and actionable surgery.
AB - Purpose: Pancreatic cancer is among the most aggressive malignancies and is rarely discovered early. However, pancreatic “incidentalomas,” particularly cysts, are frequently identified in asymptomatic patients through anatomic imaging for unrelated causes. Accurate determination of the malignant potential of cystic lesions could lead to life-saving surgery or spare patients with indolent disease undue risk. Current risk assessment of pancreatic cysts requires invasive sampling, with attendant morbidity and sampling errors. Here, we sought to identify imaging biomarkers of high-risk pancreatic cancer precursor lesions. Experimental Design: Translocator protein (TSPO) expression, which is associated with cholesterol metabolism, was evaluated in premalignant and pancreatic cancer lesions from human and genetically engineered mouse (GEM) tissues. In vivo imaging was performed with [18F]V-1008, a TSPO-targeted PET agent, in two GEM models. For image-guided surgery (IGS), V-1520, a TSPO ligand for near-IR optical imaging based upon the V-1008 pharmacophore, was developed and evaluated. Results: TSPO was highly expressed in human and murine pancreatic cancer. Notably, TSPO expression was associated with high-grade, premalignant intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanIN) lesions. In GEM models, [18F]V-1008 exhibited robust uptake in early pancreatic cancer, detectable by PET. Furthermore, V-1520 localized to premalignant pancreatic lesions and advanced tumors enabling real-time IGS. Conclusions: We anticipate that combined TSPO PET/IGS represents a translational approach for precision pancreatic cancer care through discrimination of high-risk indeterminate lesions and actionable surgery.
UR - http://www.scopus.com/inward/record.url?scp=85101194003&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101194003&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-1214
DO - 10.1158/1078-0432.CCR-20-1214
M3 - Article
C2 - 32933996
AN - SCOPUS:85101194003
SN - 1078-0432
VL - 26
SP - 5914
EP - 5925
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -