In the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular... Show moreIn the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular properties of highly aggressive cells (Cancer Stem Cells, CSCs) dispersed within the tumor represents a challenge for the identification of new efficient therapies. In most of the cases, current treatments are indeed successful in eradicating the primary tumor. However, the clinical evidence of relapse and the occurrence of therapy resistance, suggest the presence of subpopulation of cells within the tumor, that can survive such treatments and can perpetuate the cancer. In this thesis we investigated the molecular properties of selected highly aggressive CSCs and indentified novel modulators responsible for the maintenance of their aggressive behavior. Collectively, the studies described in this thesis have increased our insights into the molecular properties of highly metastatic and tumorigenic prostate cancer stem-like cells and provided new targets for possible diagnostic and therapeutic applications. Show less
Cancer and fibrosis are devastating diseases of high mortality rate and with limited curative therapies available. A better understanding of the biological drivers of these diseases is fundamental... Show moreCancer and fibrosis are devastating diseases of high mortality rate and with limited curative therapies available. A better understanding of the biological drivers of these diseases is fundamental in order to develop effective therapeutics. At the molecular level, signaling pathways control cell growth, differentiation or apoptosis during development and adult life of the organism ensuring homeostasis. Paradoxically, the same signals are often implicated or even drive disease progression. One of the signaling pathways with key regulatory functions in homeostasis, tissue fibrosis and cancer in many organs is the TGFβ/BMP pathway. In this thesis we addressed the role and therapeutic potential of TGFβ/BMP pathway inhibition using different drug compounds that are currently towards the clinic or being tested in clinical trials. Three distinct types of inhibitors were used; small molecule inhibitors of the ALK4, 5 and 7 TGFβ receptor kinases, an antisense oligonucleotide interfering with ALK5 mRNA splicing and an ALK1 ligand trap; a peptide that contains the extracellular domain of ALK1 fused to Fc and sequesters BMP9 and BMP10. These inhibitors were used in an ex vivo human fibrosis model and in vivo mouse models of various human diseases (acute liver failure/ liver regeneration, Dupuytren's fibrosis) and cancer (prostate, liver). Show less
Purpose. To investigate whether magnesium oxide reduces the interfraction motion of the prostate and the amount of rectal filling and rectal gas, which influences prostate position during... Show morePurpose. To investigate whether magnesium oxide reduces the interfraction motion of the prostate and the amount of rectal filling and rectal gas, which influences prostate position during radiotherapy for prostate cancer.Patients and methods. From December 2008 to February 2010, 92 prostate cancer patients scheduled for intensity-modulated radiotherapy (77 Gy in 35 fractions) using fiducial marker-based position verification were randomly assigned to receive magnesium oxide (500 mg twice a day) or placebo during radiotherapy. In a previous study, we investigated the effect on intrafraction motion and did not find a difference between the treatment arms. Here, we compared the interfraction prostate motion between the two treatment arms as well as the amount of rectal filling and rectal air pockets using pretreatment planning computed tomography and magnetic resonance imagingscans.Results. There was no statistically significant difference between the treatment arms in translation and rotation of the prostate between treatment fractions, except for the rotation around the cranial caudal axis. However, the difference was less than 1 degrees and therefore considered not clinically relevant. There was no significant difference in the amount of rectal filling and rectal air pockets between the treatment arms.Conclusion. Magnesium oxide is not effective in reducing the interfraction prostate motion or the amount of rectal filling and rectal gas during external-beam radiotherapy. Therefore, magnesium oxide is not recommended in clinical practice for these purposes. Show less
Leeuwen, M. van; Efficace, F.; Fossa, S.D.; Bolla, M.; Giorgi, U. de; Wit, R. de; ... ; Radiation Oncology Grp 2014
We have developed novel fluorescence bio-imaging based automated models to screen for novel candidate targets involved in prostate cancer metastasis. Utilizing these models and adopting a... Show moreWe have developed novel fluorescence bio-imaging based automated models to screen for novel candidate targets involved in prostate cancer metastasis. Utilizing these models and adopting a functional genomics based approach; we identified SYK as a novel regulator of prostate cancer progression. We also identified functional involvement of MST1R in regulating the progression of prostate cancer. For both of these targets, there is supporting human clinical data to validate our results in prostate cancer. Show less
Dinkla, A.M.; Pieters, B.R.; Koedooder, K.; Meijnen, P.; Wieringen, N. van; Laarse, R. van der; ... ; Bel, A. 2013
Background and purpose: To determine the uncertainties in planned dose associated with catheter and organ movement during 48 hours of stepping source prostate brachytherapy.Material and methods:... Show moreBackground and purpose: To determine the uncertainties in planned dose associated with catheter and organ movement during 48 hours of stepping source prostate brachytherapy.Material and methods: Pulsed-dose. rate (PDR) prostate brachytherapy as a boost is given in 24 pulses every 2 hours, making the total treatment last 48 hours. The entire treatment is based on one plan, created on the planning CT (CT1). Two follow-up CTs (CT2 and CT3) were acquired; halfway through the treatment and at the end of treatment. On these repeat scans the catheters were reconstructed and PTV and OARs were delineated. The original treatment plan was calculated on the repeat CTs. Target coverage V-100%. D-90, dose to 2 cm(3) (D2cm(3)) of the rectum and bladder and dose to 0.1 cm(3) of the urethra were recorded from the recalculated DVHs.Results: On the two repeat CTs the V-100% decreased -1.5% and -2.3% as compared to the planning CT. For the rectum D2cm(3), the average increase was 14.8% (CT1-CT2) and 173% (CT1-CT3.). Increase in bladder D2cm(3) was on average 23.1% (CT1-CT2) and 24.8% (CT1-CT3). For the urethra D0.1cm(3) an average decrease of -2% (CT1-CT2) and -3.2% (CT2-CT3) was observed.Conclusions: Changes in target coverage during treatment were small and considered clinically irrelevant. However, an overall increase in dose to the OARs was found as compared to the planned dose, which should be taken into account during treatment planning. (C) 2012 Elsevier Ireland Ltd. All rights reserved. Show less
