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

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

doi:10.1002/hep4.1861

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

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 YinTyler Zemla, Chen Wang, Zachary Fogarty, Mark Jacobson, Bradley J. Kemp, Sudhakar K. Venkatesh, Geoffrey B. Johnson, David A. Woodrum, Ajit H. Goenka

Research output: Contribution to journal › Article › peer-review

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 ⁶⁸Ga-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, ⁶⁸Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced ⁶⁸Ga. 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 ⁶⁸Ga-PSMA-11 standardized uptake value: SUV_max (median [range] 9.2 [4.9-28.4]), SUV_mean 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 ⁶⁸Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

Original language	English (US)
Pages (from-to)	1172-1185
Number of pages	14
Journal	Hepatology Communications
Volume	6
Issue number	5
DOIs	https://doi.org/10.1002/hep4.1861
State	Published - May 2022

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Hepatology

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10.1002/hep4.1861

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Thompson, S. M., Suman, G., Torbenson, M. S., Chen, Z. M. E., Jondal, D. E., Patra, A., Ehman, E. C., Andrews, J. C., Fleming, C. J., Welch, B. T., Kurup, A. N., Roberts, L. R., Watt, K. D., Truty, M. J., Cleary, S. P., Smoot, R. L., Heimbach, J. K., Tran, N. H., Mahipal, A., ... Goenka, A. H. (2022). PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and ⁶⁸Ga-PSMA-11 PET Using Cyclotron-Produced ⁶⁸Ga. Hepatology Communications, 6(5), 1172-1185. https://doi.org/10.1002/hep4.1861

Thompson, SM, Suman, G, Torbenson, MS, Chen, ZME, Jondal, DE, Patra, A, Ehman, EC, Andrews, JC, Fleming, CJ, Welch, BT, Kurup, AN, Roberts, LR, Watt, KD, Truty, MJ, Cleary, SP, Smoot, RL, Heimbach, JK, Tran, NH, Mahipal, A , Yin, J, Zemla, T, Wang, C, Fogarty, Z, Jacobson, M, Kemp, BJ, Venkatesh, SK, Johnson, GB, Woodrum, DA & Goenka, AH 2022, 'PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and ⁶⁸Ga-PSMA-11 PET Using Cyclotron-Produced ⁶⁸Ga', Hepatology Communications, vol. 6, no. 5, pp. 1172-1185. https://doi.org/10.1002/hep4.1861

@article{8e7c4f2281d44118af474ffa2471f3a7,

title = "PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and 68Ga-PSMA-11 PET Using Cyclotron-Produced 68Ga",

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 68Ga-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, 68Ga-PSMA-11 PET was prospectively performed in patients with treatment-na{\"i}ve HCC on a digital PET scanner using cyclotron-produced 68Ga. 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 68Ga-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 68Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.",

author = "Thompson, {Scott M.} and Garima Suman and Torbenson, {Michael S.} and Chen, {Zong Ming E.} and Jondal, {Danielle E.} and Anurima Patra and Ehman, {Eric C.} and Andrews, {James C.} and Fleming, {Chad J.} and Welch, {Brian T.} and Kurup, {Anil N.} and Roberts, {Lewis R.} and Watt, {Kymberly D.} and Truty, {Mark J.} and Cleary, {Sean P.} and Smoot, {Rory L.} and Heimbach, {Julie K.} and Tran, {Nguyen H.} and Amit Mahipal and Jun Yin and Tyler Zemla and Chen Wang and Zachary Fogarty and Mark Jacobson and Kemp, {Bradley J.} and Venkatesh, {Sudhakar K.} and Johnson, {Geoffrey B.} and Woodrum, {David A.} and Goenka, {Ajit H.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.",

year = "2022",

month = may,

doi = "10.1002/hep4.1861",

language = "English (US)",

volume = "6",

pages = "1172--1185",

journal = "Hepatology Communications",

issn = "2471-254X",

publisher = "Lippincott Williams and Wilkins",

number = "5",

}

TY - JOUR

T1 - PSMA as a Theranostic Target in Hepatocellular Carcinoma

T2 - Immunohistochemistry and 68Ga-PSMA-11 PET Using Cyclotron-Produced 68Ga

AU - Thompson, Scott M.

AU - Suman, Garima

AU - Torbenson, Michael S.

AU - Chen, Zong Ming E.

AU - Jondal, Danielle E.

AU - Patra, Anurima

AU - Ehman, Eric C.

AU - Andrews, James C.

AU - Fleming, Chad J.

AU - Welch, Brian T.

AU - Kurup, Anil N.

AU - Roberts, Lewis R.

AU - Watt, Kymberly D.

AU - Truty, Mark J.

AU - Cleary, Sean P.

AU - Smoot, Rory L.

AU - Heimbach, Julie K.

AU - Tran, Nguyen H.

AU - Mahipal, Amit

AU - Yin, Jun

AU - Zemla, Tyler

AU - Wang, Chen

AU - Fogarty, Zachary

AU - Jacobson, Mark

AU - Kemp, Bradley J.

AU - Venkatesh, Sudhakar K.

AU - Johnson, Geoffrey B.

AU - Woodrum, David A.

AU - Goenka, Ajit H.

PY - 2022/5

Y1 - 2022/5

N2 - 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 68Ga-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, 68Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced 68Ga. 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 68Ga-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 68Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

AB - 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 68Ga-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, 68Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced 68Ga. 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 68Ga-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 68Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

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DO - 10.1002/hep4.1861

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

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