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Title: Molecular Imaging of Metabolic Processes and the Type 1 Cannabinoid Receptor in Prostate Carcinoma
Other Titles: Moleculaire Beeldvorming van Metabole Processen en de Type 1 Cannabinoïd Receptor in Prostaatcarcinoom
Authors: Emonds, Kimy
Issue Date: 22-Oct-2012
Abstract: Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men and is the sixth leading cause of cancer-related death worldwide. Despite the fact that many patients are initially treated in curative intent by means of radical prostatectomy (RP) and/or radiotherapy (RT), disease relapse is experienced in 30-50% of all patients within 10 years. In most cases, androgen deprivation (AD) is then primarily offered to manage PCa. Unfortunately, over time therapeutic resistance develops, a state termed as castration-resistant PCa (CRPC), which demands a change of treatment. To adequately detect and follow-up patient’s condition, molecular imaging with positron emission tomography (PET) offers the advantage to visualize primary as well as recurrent PCa non-invasively. Until now, cancer imaging with PET is mainly performed with the radiolabeled glucose analogue 18F-fluorodeoxyglucose (18F-FDG) since the uptake of this tracer reflects the inherently increased glucose demand of tumour cells; however due to the limited use of 18F-FDG for PCa detection, 11C-choline and 11C-acetate have been studied and seem to be more suited for PET imaging of PCa. Though both tracers show a good and comparable diagnostic performance in patients, 11C-choline is currently used for the detection of PCa recurrences and therapy response assessment. In context of evaluating response to AD, the question still remains whether AD alters the efficiency of PET. As previous efforts have not been able to unravel this research topic precisely, it is currently not known whether discontinuing this treatment has to be done in order to maximize the accuracy of PET for assessing therapeutic success. Also, it is currently unclear if other metabolic tracers besides 11C-choline are more suitable for defining tumour response to AD. In this project, we started to examine the effect of androgen on the uptake of 18F-FDG, 11C-choline and 11C-acetate in PCa in order to define the accuracy of each tracer for detecting response to AD.In a first study, androgen-controlled uptake of 18F-FDG, 11C-choline and 11C-acetate was studied in vitro in five PCa cell lines – androgen-sensitive (PC346C, LNCaP) and androgen-independent (22Rv1, PC-3, PC346DCC) – of which each reflects a different stage of the disease (Chapter II). In the first part of this study, the uptake of the metabolic tracers as compared with the uptake in a reference cell line i.e. benign prostatic hyperplasia cell line (BPH-1) was evaluated in all cancer cell lines under androgen ablation. Whereas the relative 18F-FDG uptake showed a high variability among the cell lines, an increased relative uptake of 11C-choline and especially 11C-acetate was observed in every PCa cell line. In the second part, the effect of androgen (10-8M R1881, 10-10M R1881), bicalutamide (10-6M casodex) and the combination of both compounds (10-10M R1881 plus 10-6M casodex) was studied in all cell lines. Androgen modulated 18F-FDG uptake in LNCaP, PC346C and 22Rv1 cells, and 11C-choline uptake in the PC346C and 22Rv1 cell line, whereas no effect was observed in PC-3 and PC346DCC cells. In spite of the biological differences regarding androgen-responsiveness and AR subtype expression among these cell lines, 11C-acetate uptake was unaffected by androgen. Based on our findings, this study confirmed the poor potential of 18F-FDG for imaging PCa following AD. In addition, the androgen-independent uptake of 11C-acetate suggested that this tracer may be more suited for monitoring PCa after treatment. Nevertheless, it should be taken into account that these results need to be verified in vivo so that the preclinical findings can be translated to the clinical setting.This was also the reason to set up our second study (Chapter III). In this study, the effect of AD by means of surgical castration on metabolic µPET imaging was studied in vivo. Androgen-controlled effects on 18F-FDG, 11C-choline and 11C-acetate uptake were determined in the androgen-sensitive LAPC-4 and androgen-independent 22Rv1 xenograft PCa mouse model, which reflects respectively primary PCa and PCa undergoing biochemical failure. Whereas no significant androgen-induced effect on metabolic µPET imaging was observed in LAPC-4 tumours, AD significantly decreased 11C-choline uptake and tended to decrease 18F-FDG uptake in 22Rv1 tumours. Yet in both PCa xenograft models 11C-acetate uptake remained unaffected by androgen. For this, we suggested that 18F-FDG and 11C-choline PET could underestimate the viability of advanced tumours early after AD treatment. Furthermore, in accordance with our previous data 11C-acetate uptake seemed to occur androgen-independently and may therefore have potential for detecting PCa following AD. Despite metabolic PET imaging has shown its clinical utility, the diagnostic value of novel biological targets for cancer and in specific PCa need to be evaluated. Therefore, in the final study of this thesis we focussed on evaluating a target of interest i.e. CB1R in context of PCa PET imaging. A prospective study was set up to evaluate the feasibility of CB1R PET imaging in patients with primary and metastatic PCa (Chapter IV). For this, the high selectivity and affinity tracer 18F-MK-9470 was used. The study showed no increased 18F-MK-9470 uptake in locally-confined primary PCa and bone metastases in the axial skeleton. Yet, as compared to 18F-MK-9470 uptake in contralateral normal bone, 18F-MK-9470 PET could visualize metastases in the appendicular skeleton. From these pilot observations, we concluded that it seems unlikely that 18F-MK-9470 PET will play a significant diagnostic role for evaluating and staging PCa. Nevertheless, future studies in larger patient populations could unravel the heterogeneity regarding CB1R expression in prostate tumours in order to further determine the potential value of CB1R in the prognostic and therapeutic window.
Publication status: accepted
KU Leuven publication type: TH
Appears in Collections:Laboratory of Lipid Metabolism and Cancer (+)
Nuclear Medicine & Molecular Imaging

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