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
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
Jongkamp, V.G.; Roeloffzen, E.M.A.; Monninkhof, E.M.; Leeuw, J.R.J. de; Nijeholt, A.A.M.L.A.; Vulpen, M. van 2012
The aim of this work was to develop methods to measure structural changes in the skeleton using MicroCT. In addition, these new methods should be able to quantify biologically relevant changes. In... Show moreThe aim of this work was to develop methods to measure structural changes in the skeleton using MicroCT. In addition, these new methods should be able to quantify biologically relevant changes. In order to do this, normalized methods to analyse MicroCT scans and perform quantitative measurements within these datasets are described in this thesis. These techniques were combined with a biological angiogenesis assay and used as research tools in a study comparing various different combination treatments of bone metastases. Show less
The skeleton is one of the most common organs to be affected by metastatic disease. However, only a restricted number of solid cancers, especially those of the breast and prostate, are responsible... Show moreThe skeleton is one of the most common organs to be affected by metastatic disease. However, only a restricted number of solid cancers, especially those of the breast and prostate, are responsible for the majority of the bone metastases. Bone metastases are a major cause of morbidity, characterized by severe pain and high incidence of fractures, spinal cord compression and bone marrow aplasia requiring hospitalization. Despite the high frequency of skeletal metastases, the molecular mechanisms underlying the predisposition for tumors to colonize bone are poorly understood and treatment options are often unsatisfactory. The focus of this thesis was to better understand the processes that contribute to the formation of distant metastasis (chapter 2), particularly to bone (chapter 4__7), as well as to explore new treatment strategies with conventional (chapter 4 and 5) and novel therapeutic molecules (chapter 6 and 7) using optical imaging to sensitively monitor growth, dissemination and metastasis in mouse models (chapter 3__7). Show less
