Hormonal dependence of human prostate tumors transplantable in nude mice : the importance of low androgen levels in prostate tumor growth

The studies presented in this thesis provide experimental data which could contribute to the discussion on whether adrenal androgens are, directly or indirectly, capable of inducing growth stimulation of human prostate tumor tissue. Hormonal titration experiments were conducted to investigate whether there is a critical androgen level for growth stimulation of human prostate tumors and whether or not this threshold level exceeds the androgen levels found in castrated men (Chapters 5 and 7). Since the adrenals of rodents do not secrete androgens (Chapter 6), castration of the mouse can be regarded as total androgen withdrawal. The effect of adrenal androgens on human prostate tumor growth was studied in PC-82 tumorbearing mice supplemented with adrenal androgens, androstenedione and dehydroepiandrosterone (DHEA) (Chapters 7 and 8). In the general discussion (Chapter 10) an attempt is made to integrate experimental data and the derived ideas presented in this thesis with clinical experience on prostate cancer. Hopefully this thesis will contribute to a better understanding of the mechanisms of androgen regulated growth of human prostatic carcinoma which, together with the outcome of the necessary future experiments with human xenograft models, will result in a more effective treatment of patients with advanced prostatic cancer

Patient-derived xenograft models in cancer research

This series of 12 articles, consisting of 9 original articles and 3 reviews, is presented by international leaders in translational cancer research [...

Novel patient-derived 3D culture models to guide clinical decision-making in prostate cancer

Castration-resistant prostate cancer remains an incurable disease. The unmet clinical need to optimally select individual treatment options, and thereby maximize survival benefit, can be addressed by patient-specific preclinical models. Patient-derived organoids preserve original tumor characteristics and have shown potential for high-throughput assessments and coclinical drug testing, as highlighted for several cancer types in this review. This new patient-derived 3D culture technique and its downstream applications are the subjects of intense investigation in prostate cancer. Although challenges are not trivial, we expect a major impact on prostate cancer research, with a window of opportunities for early bench-to-bedside translation of new drug discoveries and guidance of patient-tailored disease management

Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues

Prostate Cancer (PC) is a type of cancer that is often diagnosed at very early stages due to improved detection among man in the Western world. Current imaging techniques are not optimal to determine extent of minimal early stage PC even though this is of great clinical importance. Human PC and high-grade PIN have shown high Gastrin-Releasing Peptide Receptor (GRPR) expression, while normal prostate tissue and BPH revealed to be predominantly GRPR-negative. Radiolabelled Gastrin-Releasing Peptide (GRP) or bombesin (BN) analogues targeting the GRPR can be used as non-invasive tools to diagnose, monitor and potentially treat PC. These BN analogues have already proven to be able to image PC in both tumour-bearing mice and clinical patients showing no important side effects. It's desirable that new peptides require fast-track standardised comparative testing in relevant PC models to select the best performing BN analogues for further evaluation in patients. Although knowledge about GRPR expression and development of new BN analogues can be extended, it is time to study performance of BN analogues for peptide receptor based imaging in patients validating results of PC imaging using histopathology as a golden standard

Determination of Ki-67 defined growth fraction by monoclonal antibody MIB- I in formalin-fixed, paraffin-embedded prostatic cancer tissues

The applicability of MIB‐1, a monoclonal antibody directed against the Ki‐67 antigen, was studied in the PC‐82 and LNCaP prostatic tumor models at various levels of proliferative activity. Statistically significant correlations were found in LNCaP cultures between Ki‐67 and MIB‐1 scores (r = 0.84, P < 0.001), and in PC‐82 tumors between MIB‐1 scores and paraffin tissue Ki‐67 (pKi‐67) (r = 0.90, P < 0.001), frozen tissue Ki‐67 (fKi‐67) (r = 0.86, P < 0.001), and BrdU uptake (r = 0.70, P < 0.001), respectively. pKi‐67 scores were double the fKi‐67 scores, which may be due to methodological differences. MIB‐1 scores exceeded both the fKi‐67 and pKi‐67 scores. The affinity of MIB‐1 for the antigen is much higher than the affinity of Ki‐67, which may explain the differences. MIB‐1 is a promising means of evaluating the presence of only minute amounts of the Ki‐67 antigen in paraffin‐embedded human tumor material, especially in relatively slowly growing tumors

GRPR versus PSMA:expression profiles during prostate cancer progression demonstrate the added value of GRPR-targeting theranostic approaches

Introduction: Central to targeted radionuclide imaging and therapy of prostate cancer (PCa) are prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals. Gastrin-releasing peptide receptor (GRPR) targeting has been proposed as a potential additional approach for PCa theranostics. The aim of this study was to investigate to what extent and at what stage of the disease GRPR-targeting applications can complement PSMA-targeting theranostics in the management of PCa. Methods: Binding of the GRPR- and PSMA-targeting radiopharmaceuticals [177Lu]Lu-NeoB and [177Lu]Lu-PSMA-617, respectively, was evaluated and compared on tissue sections of 20 benign prostatic hyperplasia (BPH), 16 primary PCa and 17 progressive castration-resistant PCa (CRPC) fresh frozen tissue specimens. Hematoxylin-eosin and alpha-methylacyl-CoA racemase stains were performed to identify regions of prostatic adenocarcinoma and potentially high-grade prostatic intraepithelial neoplasia. For a subset of primary PCa samples, RNA in situ hybridization (ISH) was used to identify target mRNA expression in defined tumor regions. Results: The highest median [177Lu]Lu-NeoB binding was observed in primary PCa samples, while median and overall [177Lu]Lu-PSMA-617 binding was highest in CRPC samples. The highest [177Lu]Lu-NeoB binding was observed in 3/17 CRPC samples of which one sample showed no [177Lu]Lu-PSMA-617 binding. RNA ISH analyses showed a trend between mRNA expression and radiopharmaceutical binding, and confirmed the distinct GRPR and PSMA expression patterns in primary PCa observed with radiopharmaceutical binding. Conclusion: Our study emphasizes that GRPR-targeting approaches can contribute to improved PCa management and complement currently applied PSMA-targeting strategies in both early and late stage PCa.</p