Date of Award

1-1-2019

Publication Type

Doctoral Thesis

Degree Name

Ph.D.

Department

Biological Sciences

Keywords

Glucose uptake, Neuroendocrine prostate cancer, Patient-derived xenograft models, PET Molecular Imaging, Prostate cancer, Prostate specific membrane antigen

Supervisor

Lisa Porter

Rights

info:eu-repo/semantics/openAccess

Abstract

The main treatment option for castration-resistant prostate cancer (CRPC) is androgen receptor pathway inhibition (ARPI). Selection pressure and lineage plasticity of ARPI could lead to neuroendocrine (NE) differentiation of prostate cancer (PC), promoting the more prevalent subtype of CRPC which is termed treatment-induced neuroendocrine prostate cancer (NEPC) or t-NEPC. Treatment options for NEPC are limited to platinum- and cisplatin-based combinations and median survival of NEPC patients is much lower than patients with CRPC. Early identification of NEPC and novel targeting options could be valuable. The transmembrane protein prostate-specific membrane antigen (PSMA) is an appealing target for molecular imaging and therapy of PC since it is over-expressed in a majority of PC tumors and metastatic lesions. Targeting PSMA is feasible by a wide variety of radio-ligands. The PSMA ligands can also be labeled with therapeutic radionuclides which can irradiate PSMA-expressing cells. Despite the positive implications of PSMA for many forms of advanced AdPC there are clinical reports supporting that PSMA-targeted imaging is not able to delineate NEPC tumors. Previous clinical reports indicate that PCs with a phenotype related to NE tumors can be more responsive to imaging by 18F-Fluorodeoxyglucose (FDG) rather than PSMA-targeting radioligands. In this work, 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. We use data mining approaches, cell lines and patient-derived xenograft (PDX) models 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. 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, enhanced expression of GCK and low expression of SLC2A12 correlated with NE histopathology and PSMA gene suppression. GLUT12-suppression and enhanced expression of glucokinase were 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. In summary, a NE gene signature in NEPC and NELPC associates with a distinct transcriptional profile of GLUTs and HKs. In transcriptomic level, PSMA-suppression correlates with GLUT12-suppression and glucokinase-upregulation. 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.

Download

Share

COinS