PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and 68 Ga-PSMA-11 PET Using Cyclotron-Produced 68 Ga.

Abstract

Prostate-specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68 Ga-PSMA-11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68 Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced 68 Ga. Uptake was graded qualitatively and semi-quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor-associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10-5 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = -0.753; P = 1.58 × 10-6 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68 Ga-PSMA-11 standardized uptake value: SUVmax (median [range] 9.2 [4.9-28.4]), SUVmean 4.7 (2.4-12.7), and tumor-to-liver background ratio 2 (1.1-11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68 Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

• Authors: Scott M Thompson, Garima Suman, Michael S Torbenson, Zong-Ming E Chen, Danielle E Jondal, Anurima Patra, Eric C Ehman, James C Andrews, Chad J Fleming, Brian T Welch, Anil N Kurup, Lewis R Roberts, Kymberly D Watt, Mark J Truty, Sean P Cleary, Rory L Smoot, Julie K Heimbach, Nguyen H Tran, Amit Mahipal, Jun Yin, Tyler Zemla, Chen Wang, Zachary Fogarty, Mark Jacobson, Bradley J Kemp, Sudhakar K Venkatesh, Geoffrey B Johnson, David A Woodrum, Ajit H Goenka
• Journal: Hepatology communications (Hepatol Commun) Vol. 6 Issue 5 Pg. 1172-1185 (05 2022) ISSN: 2471-254X [Electronic] United States
• PMID: 34783177 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Chemical References

• Gallium Radioisotopes
• RNA, Messenger

Topics

• Bile Duct Neoplasms
• Bile Ducts, Intrahepatic (metabolism)
• Carcinoma, Hepatocellular (diagnostic imaging)
• Cyclotrons
• Gallium Radioisotopes
• Humans
• Immunohistochemistry
• Liver Neoplasms (diagnostic imaging)
• Male
• Positron Emission Tomography Computed Tomography (methods)
• Positron-Emission Tomography
• Prostatic Neoplasms (metabolism)
• RNA, Messenger
• Theranostic Nanomedicine