SPOREs
Prostate
Projects
Projects
Project 1: Molecular Signatures of Lethal and Indolent Prostate Cancer
Co-Principal Investigators:
Philip W. Kantoff, MD
Hans-Olov Adami, MD, PhD
Mark A. Rubin, MD
Participating Institution(s):
Dana-Farber Cancer Institute
Harvard School of Public Health
Joan & Sanford I. Weill Medical College of Cornell University
Project 1: Specific Aims
One of the main challenges for medicine in the early part of 21st century is to incorporate knowledge of the human genome into the medical management of patients, thereby yielding more precise diagnoses and mechanism-based deployment of therapy. Nowhere is this need more pressing than in the treatment of men with prostate cancer. Prostate cancer is a major cause of death and morbidity, yet large numbers of men are believed to harbor tumors that are indolent even in the absence of therapy. As such, many men receive unnecessary treatment with its attendant effects, and others die of disease despite aggressive therapy. We hypothesize that the variability in the natural history of CaP is determined by heretofore unrecognized molecular heterogeneity of the disease. We therefore propose here to identify a gene expression signature that distinguishes indolent from lethal disease.
This Project has three Specific Aims:
Aim 1: Collect, register, and process archival formalin-fixed paraffin embedded (FFPE) samples from the Swedish Watchful Waiting (WW) cohorts with up to 30 years clinical follow up.
Aim 2: Develop molecular signatures of lethal and indolent prostate cancer on the Watchful Waiting FFPE samples using an Illumina expression array platform with over 6000 genes developed specifically for molecular signature discovery.
Aim 3: Validate the signatures on Swedish WW cases not used in Aim 2 and test for the presence of these profiles in tumor samples (n=100) from the Physicians’ Health Study (PHS).
At the conclusion of this proposal, we expect to have discovered and validated molecular predictors of prostate cancer outcome that are appropriate for further clinical development. To accomplish these goals, we have assembled a multidisciplinary team of investigators with a long track record of collaboration, and with particular expertise in the clinical, pathological and epidemiological aspects of prostate cancer, in the development and deployment of genomics technologies, and in advanced computational and statistical analysis.
Project 1: Studies and Results
Project 1 has made excellent progress over the first year. Aim 1 has been successfully accomplished. We have collected, registered, and processed 354 archival formalin-fixed paraffin embedded (FFPE) samples from the Swedish Watchful Waiting (WW) cohorts with up to 30 years clinical follow up. After careful deliberation, we have selected a case control design for this experiment. We therefore defined lethal prostate cancer as cases of men who died of prostate cancer or developed metastatic disease. The indolent controls were defined as men who lived a minimum of 10 years without disease progression.
We have successfully performed expression profiling on over 500 prostate cancer cases using the DASL Illumina platform. Each case was also characterized for TMPRSS2-ETS fusion status. The expression profiles of these cases have now led to a molecular signature of TMPRSS2-ERG prostate cancer. We also have a manuscript in press at JNCI describing this signature in the Swedish Watchful Waiting cohort. This work was also presented at 2008 Annual AACR meeting during the Prostate Cancer Organ System Seminar (April 15, 2008).
Using the expression array data already generated and deposited on GEO (publicly available), we are currently working on defining a signature of lethal and indolent prostate cancer (Aim 2). This has required that we perform some additional analysis on samples from patients who developed disease progression. We are trying to work out the significant effect that prostate cancer heterogeneity may play on the development of a molecular signature of aggressive prostate cancer.
Project 1: Significance
Our proposal is attempting to develop molecular test that will be able to tell a patient at time of initial diagnosis the risk they have of having aggressive prostate cancer. We have made an important observation that recently identified “on” switch called gene fusion is significantly associated with disease progression. By identifying these cases and comparing them with cases that are in the “off” state, we are now able to ask what other genes and gene pathways are perturbed by turning the gene fusion on. These findings need to be confirmed in other data sets and by performing experiments in animal and cell line models.
Project 1: Plans
Our original hypothesis that a molecular signature could distinguish indolent from aggressive prostate cancer was not confirmed after performing the original analysis. We are currently attempting to expand the original Aims 2 and 3 by developing gene expression data on pairs of prostate cancer samples from the original diagnosis and from patients who went on to die of prostate cancer. This pair-wise analysis will allow us to determine to what extent the aggressive signature is present at the time of initial diagnosis. We will attempt to identify up to 25 paired cases from the Swedish Cohort. We will also expand the number of cases profiled to include over 700 cases from the non-extreme cases. This will allow us to re-analyze the data on approximately 1000 prostate cancers from the Watchful Waiting Cohort.
Data that emerged from this study also suggests that we can use TMPRSS2-ETS fusion status to help distinguish indolent from aggressive prostate cancer. In addition, the novel finding that ER may play a critical role in disease progression, we are planning to test a chemopreventive cohort composed of 1500 cases treated by a selective ER-alpha antagonist, which would be supported by Industry.
Project 1: Publications
TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort.
Demichelis F, Fall K, Perner S, Andrén O, Schmidt F, Setlur SR, Hoshida Y, Mosquera JM, Pawitan Y, Lee C, Adami HO, Mucci LA, Kantoff PW, Andersson SO, Chinnaiyan AM, Johansson JE, Rubin MA. Oncogene. 2007 Jul 5;26(31):4596-9. Epub 2007 Jan 22. Erratum in: Oncogene. 2007 Aug 16;26(38):5692
Setlur S, Mertz K, Hoshida Y, Demichelis F, Lupien M, Perner S, Sboner A, Pawitan Y, Andren O, Johnson L, Tang J, Adami HO, Calza S, Chinnaiyan AM, Rhodes DR, Tomlins S, Fall K, Mucci LA, Kantoff PW, Stampfer MJ, Andersson SO, Varenhorst E, Johansson JE, Brown M, Golub TR, Rubin MA. Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):815-25. Epub 2008 May 27.
Testing a multigene signature of prostate cancer death in the Swedish Watchful Waiting Cohort
Mucci LA, Pawitan Y, Demichelis F, Fall K, Stark JR, Adami HO, Andersson SO, Andrén O, Eisenstein A, Holmberg L, Huang W, Kantoff PW, Kim R, Perner S, Stampfer MJ, Johansson JE, Rubin MA. Cancer Epidemiology Biomarkers & Prevention 17, 1682-1688, July 1, 2008. Published Online First June 26, 2008
Nine-gene molecular signature is not associated with prostate cancer death in a watchful waiting cohort.
Mucci LA, Pawitan Y, Demichelis F, Fall K, Stark JR, Adami HO, Andersson SO, Andrén O, Eisenstein AS, Holmberg L, Huang W, Kantoff PW, Perner S, Stampfer MJ, Johansson JE, Rubin MA. Cancer Epidemiol Biomarkers Prev. 2008 Jan;17(1):249-51.
Project 1: Project Generated Resources
We have created several unique resources that are now available to our Prostate Cancer SPORE investigators. These include, Tissue Microarrays from all extreme cases from the Swedish Watchful Waiting Cohort, DNA samples for project 2, and RNA for future studies. We have also developed expression profiling data on over 6000 gene from over 350 cases from Sweden and 100 cases from the US that will become publicly available at time of publication (June 2008). This data set includes all information used for the JNCI publication.
