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Abstract
Although the incidence of de novo neuroendocrine prostate cancer (PC) is rare, recent data suggest that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine hallmarks and androgen receptor (AR) suppression in PC. Previous clinical reports indicate that PCs with a phenotype similar to neuroendocrine tumors can be more amenable to imaging by 18F-FDG than by PSMA-targeting radioligands. In this study, we evaluated the association between neuroendocrine gene signature and 18F-FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported 18F-FDG avidity of PSMA-suppressed tumors. Methods: Data-mining approaches, cell lines, and patient-derived xenograft models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes HK1-HK3 and GCK), and PSMA (FOLH1 gene) after AR inhibition and in correlation with neuroendocrine hallmarks. Also, we characterize a neuroendocrine-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no neuroendocrine histopathology. We measured glucose uptake in a neuroendocrine-induced in vitro model and a zebrafish model by nonradioactive imaging of glucose uptake using a fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrated that a neuroendocrine gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR inhibitors, high expression of GCK and low expression of SLC2A12 correlated with neuroendocrine histopathology and PSMA gene suppression. GLUT12 suppression and upregulation of glucokinase were observed in neuroendocrine-induced PC cell lines and patient-derived xenograft models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: A neuroendocrine gene signature in neuroendocrine PC and NELPC associates with a distinct transcriptional profile of GLUTs and hexokinases. PSMA suppression correlates with GLUT12 suppression and glucokinase upregulation. Alteration of 18F-FDG uptake-associated genes correlated positively with higher glucose uptake in AR- and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient preclinical method for monitoring nonradioactive glucose uptake.

Affiliations

Martin K Bakht  1   2   3 , Jessica M Lovnicki  4 , Janice Tubman  1 , Keith F Stringer  1   5 , Jonathan Chiaramonte  6 , Michael R Reynolds  6 , Iulian Derecichei  1 , Rosa-Maria Ferraiuolo  7 , Bre-Anne Fifield  1 , Dorota Lubanska  1 , So Won Oh  2   3 , Gi Jeong Cheon  8   3 , Cheol Kwak  9 , Chang Wook Jeong  9 , Keon Wook Kang  2   3 , John F Trant  6 , Colm Morrissey  10 , Ilsa M Coleman  11 , Yuzhuo Wang  4 , Hojjat Ahmadzadehfar  12 , Xuesen Dong  4 , Lisa A Porter  13
1 Department of Biomedical Sciences, University of Windsor, Windsor, Ontario, Canada.
2 Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
3 Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
4 Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
5 Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
6 Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
7 Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
8 Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea larrycheon@snu.ac.kr lporter@uwindsor.ca.
9 Department of Urology, Seoul National University College of Medicine, Seoul, Korea.
10 Department of Urology, University of Washington, Seattle, Washington.
11 Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington; and.
12 Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany.
13 Department of Biomedical Sciences, University of Windsor, Windsor, Ontario, Canada larrycheon@snu.ac.kr lporter@uwindsor.ca.