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Project

Clinical and preclinical studies of modulators of high-risk prostate cancer with metastatic potential

The overarching aim of this dissertation is to contribute to both clinical and preclinical knowledge of high-risk localized prostate cancer (PCa). 

It is currently accepted that high-risk PCa patients need radical treatment in an attempt to cure their disease. However, there are still important questions related to both oncological and functional outcomes that need to be addressed:

-       Currently, the EAU PCa guidelines recommend both external beam radiation therapy (EBRT) to a dose of 76-78 Gy or EBRT + brachytherapy boost (high- or low-dose rate) both with long-term androgen deprivation therapy or radical prostatectomy in men with localized high-risk or locally advanced PCa and a life expectancy of > 10 years. Although multiple therapeutic options are available, there is no evidence on which treatment modality is superior based on both oncological and non-oncological outcomes. We will perform a systematic review of the literature to evaluate the benefits and harms of primary local treatment of high-risk and locally advanced PCa and analyze whether any differences exist between certain subpopulations (chapter 3). 

-       We will also specifically focus on a more in-depth evaluation of some of the modalities of radical prostatectomy in chapter 4. We will investigate the effect of nerve-sparing RP on oncological outcomes in localised PCa. Preservation of the neurovascular bundle has a beneficial effect on several functional outcomes like erectile function. However, this can only be attempted if oncological survival is guaranteed. In a systematic review, we will explore patient treated with RP with or without neurovascular bundle preservation and evaluate the effect positive surgical margins and biochemical recurrence. 

-       We will evaluate which pathological features would negatively impact PCa survival after radical prostatectomy in a large retrospective study of more than 1000 patient (EMPaCT database). The main focus is to define the impact of positive lymph node burden on survival of patient in the setting of high-risk PCa (chapter 5). 

One of the true challenges in translational cancer research is the understanding of the role of certain (mutated) genes and their contributions to the evolution of the disease. For primary high-risk PCa tumors such research can help to identify a clinically strong metastatic potential which can in turn guide future therapeutic interventions and follow-up schemes. Here, we hypothesized that the primary tumor already harbors genomic signatures for metastatic potential. The objective of the translational part of this dissertation follows from an earlier genomic analysis of a highly selected retrospective high-risk PCa population with long-term follow-up (PhD thesis by T. Van den Broeck). The integrated CNA and gene expression analysis resulted in the detection of several genes that were differentially expressed between the recurrent (case) and non-recurrent (control) group. We will explore the molecular physiology and link with cancer and more particularly with metastatic development of two genes of interest: antizyme inhibitor 1 (AZIN1) and exportin 1 (XPO1).  

Given the clear association between AZIN1 expression levels in the primary tumor with metastatic recurrence at long term follow-up, in chapter 6 we hypothesize that it might enhance a pro-growth and pro-migratory phenotype allowing the primary tumor to metastasize to distant sites. AZIN1 is a known regulator of the polyamine production, by sequestering antizymes which interact with ODC1 for ubiquitin-independent protein degradation, resulting in an increase in polyamine levels. However, it has also polyamine-independent functions. By investigating the AZIN1-induced phenotype in prostate cancer cells, we will explore underlying mechanisms of action by which AZIN1 might affect the metastatic process. 

In chapter 7, a focal deletion of 2p15 and a lower expression of the residing XPO1 gene is highlighted, which was unique for patients who did not develop recurrent disease. This suggests a lower expression of XPO1 as a possible predictor for a reduced metastatic potential in our high-risk PCa cohort. XPO1 is one of the main nuclear exporters shuttling cargo from the nucleus to the cytoplasm and has been the target of drug development with the design of already second-generation synthetic inhibitors of nuclear export (SINE). We will use this second-generation compound, eltanexor (KPT-8602) and evaluate its effects in preclinical PCa models. 

Date:1 Aug 2016 →  29 Apr 2022
Keywords:genomics, AZIN1, XPO1, high-risk prostate cancer, matrikines, eltanexor
Disciplines:Endocrinology and metabolic diseases, Urology, Cancer biology
Project type:PhD project