PT  - JOURNAL ARTICLE
AU  - Martin K. Bakht
AU  - Jessica M. Lovnicki
AU  - Janice Tubman
AU  - Keith F. Stringer
AU  - Jonathan Chiaramonte
AU  - Michael R. Reynolds
AU  - Iulian Derecichei
AU  - Rosa-Maria Ferraiuolo
AU  - Bre-Anne Fifield
AU  - Dorota Lubanska
AU  - So Won Oh
AU  - Gi Jeong Cheon
AU  - Cheol Kwak
AU  - Chang Wook Jeong
AU  - Keon Wook Kang
AU  - John F. Trant
AU  - Colm Morrissey
AU  - Ilsa Coleman
AU  - Yuzhuo Wang
AU  - Hojjat Ahmadzadehfar
AU  - Xuesen Dong
AU  - Lisa A. Porter
TI  - Differential expression of glucose transporters and hexokinases in prostate cancer with a neuroendocrine gene signature: a mechanistic perspective for FDG imaging of PSMA-suppressed tumors
AID  - 10.2967/jnumed.119.231068
DP  - 2019 Dec 01
TA  - Journal of Nuclear Medicine
PG  - jnumed.119.231068
4099  - http://jnm.snmjournals.org/content/early/2019/12/03/jnumed.119.231068.short
4100  - http://jnm.snmjournals.org/content/early/2019/12/03/jnumed.119.231068.full
AB  - Purpose: Although the incidence of de novo neuroendocrine prostate cancer (NEPC) is rare, recent data suggests that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine (NE) hallmarks and androgen receptor (AR)-suppression in prostate cancer (PC). Previous clinical reports indicate that PCs with a phenotype similar to NE tumors can be more amenable to imaging by 18F-Fluorodeoxyglucose (FDG) rather than PSMA-targeting radioligands. In this study, we evaluated the association between NE gene signature and FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported FDG-avidity of PSMA-suppressed tumors. Methods: Data mining approaches, cell lines and patient-derived xenograft (PDX) 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 to 3 and GCK) and PSMA (FOLH1 gene) following AR-inhibition and in correlation with NE hallmarks. Also, we characterize a NE-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no NE histopathology. We measured glucose uptake in a NE-induced in vitro model and a zebrafish model by non-radioactive imaging of glucose uptake using fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrates that a NE 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 NE histopathology and PSMA gene suppression. GLUT12-suppression and amplification of glucokinase was observed in NE-induced PC cell lines and PDX models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: NE gene signature in NEPC and NELPC associates with a distinct transcriptional profile of GLUTs and HKs. PSMA-suppression correlates with GLUT12-suppression and glucokinase-amplification. Alteration of 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 pre-clinical method for monitoring non-radioactive glucose uptake.