Sub theme 3.1.2
Prostate cancer

Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff

Goals of research: general outline

A long lasting, intensive collaboration between the departments Urology, Pathology, and Reproduction & Development initiated by Fritz Schröder, has established prostate cancer as an important research area at Erasmus MC. The goal is to understand the origin and progression of prostate cancer at the molecular, mechanistic level, and to apply the gained insights into clinical practice. That is, to define and implement new molecular targets for screening, diagnosis, prognosis and treatment. Most investigators working on prostate cancer are housed in the Josephine Nefkens Institute, a situation that favors intellectual exchange, intensive collaborations and sharing of facilities.

Scientific achievements

Trapman’s group focusses on the mechanism of androgen regulation and on the role of important genetic modifications (PTEN inactivation and overexpression of ETS fusion genes) in prostate cancer.

The androgen receptor (AR) is essential in growth of primary prostate cancer. In an continuous effort to decipher the mechanism of androgen-regulated prostate cancer, and the mechanism of castrate-resistant prostate cancer. Houtsmuller and Trapman investigated the dynamics of AR function. The order of AR dimerization and cofactor interaction was determined. Moreover, it was shown that blocking of the cofactor groove in the AR ligand binding domain is an interesting novel target of prostate cancer therapy. Together with Jenster (Urology) it was found that the cofactor BAF60a directly interacts with he AR.

The previously established prostate-targeted Pten knockout mouse prostate cancer model was further characterized. Novel progenitor cells in the luminal epithelial cell layer were identified as candidate prostate tumor initiating cells. Furthermore it was shown that a Tp53 negative background in the model resulted in development of more aggressive metastatic and genetical instable prostate cancer. Inactive Tp53 gives rise to prostate tumors with inactivation of one Pten allele.

The major genetic alteration in prostate cancer is the fusion of TMPRSS2 and ERG. A TMPRSS2-ERG variant with a favorable clinical prognosis was identified. In addition, we found novel fusions between the ETV1 and ETV4 genes and several different androgen-regulated, prostate-specific partner genes. A further important observation was that ETV1 translocation can lead to a fusion gene that expresses truncated ETV1 (dETV1), or to overexpression of the wild-type ETV1gene. It was shown that full-length ETV1 is more tumorigenic than dETV1 in in vitro biological assays.

Van Leenders’ group focuses on the role of cancer stem cells in established prostate cancer by analysis of the Hepatocyte Growth Factor (HGF)/ c-met pathway. Novel molecular pathways for stem cells are also explored from prostate cancer xenografts in close collaboration with the Department of Urology. Validation of potential pathways is validated in patients’ surgical specimens. In addition, markers for disease progression and aggressiveness are explored using gene-expression arrays, and validated in a Tissue Micro Arrays (TMA) and diagnostic needle-biopsies.

Future plans: special goals and approach

Specific goals in prostate cancer are: identification of novel small molecules that inhibit AR activity and the AR target gene specificity in different stages of prostate cancer. Moreover, we will study the properties of fusion partners of ETS oncogenes and we will address the question of fusion gene selection by the ETS genes. Further we will continue the study of the difference in function between ERG, dETV1 and full-length ETV1. In the Pten model we will further analyze the properties of the tumor initiating cells and the mechanism of tumor progression.

Novel pathways specific for prostate cancer stem cells are validated in patients’ specimens, studied in culture and in appropriate mouse models to explore the role of stem cells in established disease.

Most recent publications

1.      A.O. Brinkmann and J. Trapman. Prostate cancer schemes for androgen escape. Nature Med. 6, 628-629 (2000). (IF 26.3).

2.      Dubbink H.J., Hersmus R., Verma C.S., Van der Korput H.A., Berrevoets, C.A., Van Tol J., Ziel-van der made A.C., Brinkmann A.O., Pike A.C. and Trapman J. Distinct recognition modes of FXXLF and LXXLL motifs by the androgen receptor. Mol. Endocrinol. 18, 2132-2150 (2004). (IF 5.3).

3.      Ma X., Ziel-van der made A.C., Autar B., van der Korput H.A., Vermeij M., van Duijn P., Cleutjens K.B., de Krijger R., Krimpenfort, P., Berns, A., van der Kwast T.H. and Trapman J. Targeted biallelic inactivation of Pten in the mouse prostate leads to prostate cancer accompanied by increased epithelial cell proliferation, but not by reduced apoptosis. Cancer Res. 65, 5730-5739 (2005). (IF 7.6).

4.      Hermans KG, Bressers AA, van der Korput HA, Dits NF, Jenster G, Trapman J.Two unique novel prostate-specific and androgen-regulated fusion partners of ETV4 in prostate cancer.Cancer Res 2008;68:3094-8.

5.      Hermans KG, van der Korput HA, van Marion R, van de Wijngaart DJ, Ziel-van der Made A, Dits NF, Boormans JL, van der Kwast TH, van Dekken H, Bangma CH, Korsten H, Kraaij R, Jenster G. Trapman J.Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer. Cancer Res 2008;68:7541-9.

6.      Korsten H, Ziel-van der Made A, Ma X, van der Kwast T, Trapman J. Accumulating progenitor cells in the luminal epithelial cell layer are candidate tumor initiating cells in a Pten knockout mouse prostate cancer model. PLoS One 2009 May 22;4(5):e5662.

7.      Hermans KG, Van Marion R, Van Dekken H, Jenster G, Van Weerden WM and Trapman J. TMPRSS2:ERG fusion by translocation or interstitional deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late stage androgen receptor negative prostate cancer. Cancer Res 66, 10658-10663 (2006). (IF 7.6).

8.      Van Royen M, Cunha SM, Mattern KA, Nigg A, Dubbink HJ, Trapman J, and  Houtsmuller AB. Compartmentalization of androgen receptor protein-protein interactions in living cells J Cell Biol 177, 63-72 (2007). (IF 9.5).

9.      T. Wolters, C.J. Vissers, C.H. Bangma, F.H. Schröder, G.J.L.H. van Leenders: EZH2, p27kip1 and MIB-1 on Gleason 6 biopsy specimens are valuable in selecting men with indolent prostate cancer at prostatectomy. BJU Int 2009; in press

10.  G.J.L.H. van Leenders, D. Dukers, D. Hessels, S.W. van den Kieboom, C.A. Hulsbergen, J.A. Witjes, A.P. Otte, C.J. Meijer, F.M. Raaphorst: Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol 2007; 52: 455-463

People associated with sub theme 3.1.2: Prostate cancer
Name Position Department
PhD Student  Y  Abozaid PhD-candidate Urology
PhD Student  Y  Abozaid PhD-candidate Urology
MD  S  Aluwini Senior researcher not being a workgroup leader Radiation Oncology
I.  Androulakis PhD-candidate Radiotherapy
Ladyofrage  Andryzew Senior researcher not being a workgroup leader General Surgery
ли&  Paulpeter  Arthursap Postdoc/junior researcher General Surgery
MD  F.  Atrafi PhD-candidate Medical Oncology
Drs.  I.L.  Bakker PhD-candidate Nuclear Medicine
R.  Barbosa Marques Postdoc/junior researcher Urology
Ms  L.T.B.  Bate-Eya PhD-candidate Urology
BPSI  Belderbos Assistent professor (UD) Medical Oncology
R.G.  Bijman MSc student (please specify in remarks) Radiotherapy
R.B.  Böttcher MSc student (please specify in remarks) Urology
MSc  W.M.H.  Busser Postdoc/junior researcher Radiation Oncology
Drs.  K.L.S.  Chatalic PhD-candidate Nuclear Medicine
Drs.  L.F.  van  Dessel PhD-candidate Medical Oncology
N.F.J.  Dits Technician Urology
Dr.  M.  van  Driel Senior researcher not being a workgroup leader Internal Medicine
P.W.  van  Duijn Postdoc/junior researcher Pathology
Radiotherapeute  MDF  Sr  Frelinghuysen Postdoc/junior researcher Radiation Oncology
M.A.  van  Gelder PhD-candidate Urology
JF  de  Graaf PhD-candidate Viroscience
L.M.  van der  Graaf Technician Nuclear Medicine
T.A.  Hartjes PhD-candidate Pathology
R.  van  Haveren PhD-candidate Radiation Oncology
Ladyofrage  Henryhop Professor not being a workgroup leader General Surgery
S  van  Herk Other as mentioned (please specify in remarks) Urology
S.D.  Hiltemann Postdoc/junior researcher Urology
E.  Hollemans PhD-candidate Pathology
Drs.  A.M.  Hoogland PhD-candidate Pathology
MSc.  Y.  Hoogstrate Technician Urology
DP  Hurkmans PhD-candidate Medical Oncology
Mrs  C.  Ibeawuchi PhD-candidate Urology
PhD  A.  Jamalian Nasrabadi Postdoc/junior researcher Neuro Oncology
AC  de  Jong PhD-candidate Medical Oncology
MD  I.P.E.D.  Kümmerlin Physician (MD) Pathology
MD  C.F.  Kweldam Physician (MD) Pathology
C.T.P.  van der  Lans Other as mentioned (please specify in remarks) Urology
Ladyofrage  Magmab Postdoc/junior researcher General Surgery
Dr.  E. S.  Martens-Uzunova Postdoc/junior researcher Urology
Smooveb73  Maximjnc Senior researcher not being a workgroup leader General Surgery
Msc  E.S.  de  Morrée PhD-candidate Urology
L.  Mout PhD-candidate Medical Oncology
E.  van  Munster Other as mentioned (please specify in remarks) Medical Oncology
E  Murce Silva PhD-candidate Nuclear Medicine
D.F.  Nieuwenhuijse MSc student (please specify in remarks) Urology
drs.  T.C.  Noordhoff PhD-candidate Urology
MSc  D.F.  Osses PhD-candidate Urology
I  Oujaka El Ghazouani Other as mentioned (please specify in remarks) Urology
M.W.  Paul PhD-candidate Pathology
W.  Plugge MSc student (please specify in remarks) Urology
Physician Assistant  TJ  Rick PhD-candidate Radiation Oncology
Ing  J.  van  Riet PhD-candidate Medical Oncology
I.J.  Robbesom - van den Berge Technician Internal Medicine
drs  DGJ  Robbrecht Physician (MD) Medical Oncology
Mr.  G.A.  Rodriguez Blanco PhD-candidate Neurology
L  Rossi PhD-candidate Radiation Oncology
drs  E.A.M.  Ruigrok PhD-candidate Radiotherapy
B.W.K.  Schipaanboord PhD-candidate Radiotherapy
M.  van der   Schoor Other as mentioned (please specify in remarks) Urology
Dr.  C.  Schroten-Loef Postdoc/junior researcher Medical Oncology
W.D.  Seifu MSc student (please specify in remarks) Urology
W.D.  Seifu MSc student (please specify in remarks) Urology
MD  Sert Physician (MD) Experimental Urology
A  SHARMA Physician (MD) Radiation Oncology
G  Snaterse PhD-candidate Internal Medicine
Drs.  R.J.  van  Soest PhD-candidate Urology
S.N.  Strepis MSc student (please specify in remarks) Urology
S.N.  Strepis MSc student (please specify in remarks) Urology
Dr.  R.  Temanni Postdoc/junior researcher Urology
0day Music For DJs  Paulpeter  TerryfUnny MSc student (please specify in remarks) General Surgery
A.  Van Hemelryk PhD-candidate Urology
M.  Vara Pérez MSc student (please specify in remarks) Urology
E.I.  Verhoef Technician Pathology
Ms.  C.Y.L.  Versluis PhD-candidate Experimental Urology
My up to date ascend  Tmmaverick  vickixr69 Postdoc/junior researcher General Surgery
PhD  S.  Vidic Postdoc/junior researcher Urology
M.S.  Vredenbregt-van den Berg Technician Urology  W.M.  van  Weerden Assistent professor (UD) Urology
XRumer  Paulpeter  WendellloT MSc student (please specify in remarks) General Surgery
H.J.G.  van de  Werken Assistent professor (UD) Urology
QettoE  Williamfut Workgroup leader within the School General Surgery
H.  Woldekiros MSc student (please specify in remarks) Urology
Drs.  R.C.  Wortel PhD-candidate Radiation Oncology
PhD  J.A.A.   van  Zoggel Postdoc/junior researcher Urology