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