ONCOTHESIS

Multimodality treatment for high-risk prostate cancer: New perspectives

High-risk prostate cancer represents the most aggressive form of the disease worldwide. In the past it was largely treated without curative intent but during the last years there has been a paradigm shift with an increase of curative procedures (particularly radical prostatectomy) for high-risk patients and, vice versa, active surveillance for low-risk disease. For this reason the high-risk group represents the novel target for contemporary research. The pre-operative risk groups are considered homogeneous in terms of prognosis and therapeutic response but there are grey zones within each group that have not been adequately studied. The main hypothesis of this PhD thesis (ISBN-NUMBER: 9789082757606 for the printed version and 9789082757613 for the e-version) is that not all high-risk prostate cancer patients have the same outcomes after surgery and also not the same response to multimodality therapies. In this context, novel treatments or their combinations should be tested. We analysed the largest high-risk database in the world demonstrating that not all high-risk patients after surgery have the same outcome according to their postoperative pathologic features. The European Multicentre Prostate Cancer Clinical and Translational Research group classifier was then defined as three different prognostic groups to predict cancer specific death. Interestingly, patients in these groups did not respond homogenously to adjuvant radiotherapy and/or androgen deprivation therapy. We also analysed the survival impact of neoadjuvant hormonal therapy before surgery, showing that patients who need adjuvant radiotherapy and were exposed to neoadjuvant hormonal therapy have the best prognosis. This outcome opens new perspectives for neoadjuvant treatment with or without other treatment combinations. The ARNEO trial is a phase II randomised, double blind, placebo controlled trial to study the association of apalutamide and degarelix before surgery for intermediate and high-risk disease.

(BELG J MED ONCOL 2018:12(3):130–132)

Exploring extracellular vesicles for siRNA delivery and Raman-based diagnostics

Summary

This report briefly discusses the use of extracellular vesicles in a pharmaceutical context. In the first part, the application of extracellular vesicles as a bio-inspired drug delivery carrier for small nucleic acid drugs was assessed. In this context, optimal purification strategies were evaluated and a new cargo loading method was developed for siRNA. In addition, the siRNA delivery performance of extracellular vesicles was bench-marked against a synthetic liposomal nanocarrier. In the second part, a new analysis platform based on Raman spectroscopy was developed to exploit extracellular vesicles as a biomarker source for liquid biopsies.

(BELG J MED ONCOL 2018;12(2):79–81)

Pharmacological restoration of tumour suppressor protein p53 in neuroblastoma: seeking synergy and non-invasive biomarkers

Summary

Neuroblastoma is a rare developmental tumour of young children accounting for a disproportionally high proportion of paediatric cancer deaths. Increasing insights into neuroblastoma genetics and biology led to the identification of the MDM2 antagonist idasanutlin as a promising therapeutic strategy. In this thesis, we investigated two key aspects that could facilitate the clinical implementation of idasanutlin for the treatment of neuroblastoma patients. First, we identified the BCL2 inhibitor venetoclax as a synergistic drug partner of idasanutlin using both in vitro and in vivo model systems of neuroblastoma. Second, we discovered circulating miRNAs that dynamically respond to p53 activation in mice carrying human neuroblastoma xenografts; opening up possibilities for non-invasive treatment monitoring.

(BELG J MED ONCOL 2018;12(1):26–28)

Study on tumour biology and the aging effect of chemotherapeutic treatment in older breast cancer patients

Summary

The main objective of this doctoral research was to expand the scientific knowledge on the complex interface between cancer and biological aging. In the first part, we started by studying stromal characteristics of breast cancers arising in young respectively old patients. Differences in stroma, could lead to a different behaviour of the tumour cells according to age. By laser capturing the stromal compartments of breast cancers from young and old patients, and comparing the gene expression profiles, we confirmed for the first time in humans, the presence of a Senescence Associated Secretory Profile and of Autophagy to Senescence Transition in older breast cancer stromal samples as well as differences in gene expression mainly in genes responsible for proliferation, dedifferentiation and migration into the extracellular matrix.

In the second part of the thesis, we investigated biological aging in the rest of the organism, and the impact from cancer treatment (by chemotherapy) on this process. In a retrospective study investigating several biological and clinical parameters of aging in young and old breast cancer patients, IL-6 showed to be a robust frailty marker. Next, we performed a prospective study in early breast cancer patients either or not treated with adjuvant chemotherapy, and tested if the natural evolution of clinical and/or biological aging markers was influenced by chemotherapy. We did not find convincing evidence that chemotherapy would accelerate biological aging in breast cancer patients.

(BELG J MED ONCOL 2018;12(1):29–32)

Risk factors associated with bladder cancer occurrence and recurrence: an epidemiological and clinical approach

SUMMARY

Age, gender and smoking habits are the most important risk factors for bladder cancer. Selenium supplement, in addition to standard care, does not diminish recurrence in bladder cancer patients compared to placebo and increases the risk of bladder cancer with 6% for each increase of 10 mcg/L of blood selenium level. Each extra daily portion of vegetables decreases the risk of bladder cancer with 6%. Neither diabetes nor metformin was associated with bladder cancer risk in the Clinical Practice Research Datalink.

(BELG J MED ONCOL 2017;11(8):393-395)

Role of glucocorticoid receptor-mediated effects on the colon cancer microenvironment

SUMMARY

The cancer microenvironment, which includes cancer-associated fibroblasts, plays an essential role during cancer progression. Glucocorticoids, steroidal ligands of glucocorticoid receptor, are often administered to cancer patients during chemotherapy. Glucocorticoids have a substantial effect on CAFs, affecting composition of their secretome, which results in a reduced pro-angiogenic effect and a neutralized growth- and invasion-promoting impact on cancer cells.

(BELG J MED ONCOL 2017;11(6):289–291)

Glycosylation of urinary prostate proteins and its potential diagnostic applications

SUMMARY

Prostate cancer (PCa) is the 2^nd most frequently diagnosed cancer in males worldwide and the most frequently diagnosed in Europe. Serum prostate specific antigen (sPSA) is the most commonly used biochemical test in PCa diagnosis. However, as a diagnostic parameter sPSA is associated with considerable analytical problems. As N-glycosylation patterns of sPSA show diagnostic potential, we determined if N-glycosylation of urinary prostate proteins is usable in the diagnosis of PCa. Significant differences were observed between the urinary N-glycosylation of healthy volunteers, patients with benign prostate hyperplasia (BPH) and PCa. The urinary glycosylation marker improved the diagnosis of PCa by adding them to the current models, especially in the diagnostic grey zone of sPSA concentrations between 4 and 10 μg/L. Furthermore, a link was noticed between urinary N-glycosylation and extracellular vesicles in urine. Urinary N-glycosylation could therefore be used as diagnostic and prognostic markers in PCa, although further validation of the biomarker is warranted.

(BELG J MED ONCOL 2017;11(3):126–128)