In the RFA for Molecular interaction between tumor cells and bone, one area of emphasis was that """"""""A comprehensive analysis of genetic changes occurring between primary tumor and bone metastases and the development of a tractable system to study bone metastases are needed."""""""" This application focuses on this area of emphasis by demonstrating that we have developed a method for comprehensive genetic expression analysis between both primary prostate cancer and metastatic prostate cancer but also between prostate cancer metastases that develop in bone versus soft tissue sites. This analysis has allowed us to preliminarily identify potential genes of importance that regulate prostate cancer metastasis to bone. We hypothesize that we can identify genetic changes that are important in prostate cancer metastasis to bone and determine their functional significance in prostate cancer bone metastasis. To test this hypothesis we have developed the following specific aims:
Specific Aim 1 : Characterize the expression signature of prostate metastases derived from bone versus soft tissue sites. Utilizing tissue acquired through our Rapid Autopsy Program, we will identify genes that are differentially expressed in prostate cancer metastases at the gene and tissue level.
Specific Aim 1 A: We will utilize tissue derived from multiple bone versus soft tissue sites from a variety of patients (variable genetic background).
Specific Aim 1 B: We will utilize tissue derived from multiple bone and soft tissue sites from a single patient (common genetic background).
Specific Aim 1 C: Utilize prostate cancer cell lines grown on bone matrix versus liver extracellular matrix to look at differential gene expression.
Specific Aim 2 : We will investigate the function of differentially expressed genes between bone and soft tissue metastases to determine their significance to prostate cancer metastasis to bone. We will start with the FROUNT/PERICENTRIN gene, identified in our preliminary experiments.
Specific Aim 2 A: We will study the potential significance of genes that are differentially expressed between bone and soft tissue metastases as prognostic and diagnostic markers for prostate cancer utilizing our tissue microarrays with the corresponding clinical follow-up data. In summary, we have developed an effective paradigm for identifying and characterizing genes whose expression is altered in metastatic versus primary prostate cancers. By concentrating on genetic changes between bone and soft tissue metastases, a better understanding of the molecular biology that underpins prostate cancer metastasis should be elucidated. This knowledge could lead to the development of better biomarkers of disease progression as well as targets for therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102872-02
Application #
6803233
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (M2))
Program Officer
Mohla, Suresh
Project Start
2003-09-24
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$339,482
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Mehra, Rohit; Kumar-Sinha, Chandan; Shankar, Sunita et al. (2011) Characterization of bone metastases from rapid autopsies of prostate cancer patients. Clin Cancer Res 17:3924-32
Han, Bo; Suleman, Khalid; Wang, Lei et al. (2010) ETS gene aberrations in atypical cribriform lesions of the prostate: Implications for the distinction between intraductal carcinoma of the prostate and cribriform high-grade prostatic intraepithelial neoplasia. Am J Surg Pathol 34:478-85
Han, Bo; Mehra, Rohit; Lonigro, Robert J et al. (2009) Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression. Mod Pathol 22:1083-93
Han, Bo; Mehra, Rohit; Suleman, Khalid et al. (2009) Characterization of ETS gene aberrations in select histologic variants of prostate carcinoma. Mod Pathol 22:1176-85
Laxman, Bharathi; Morris, David S; Yu, Jianjun et al. (2008) A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res 68:645-9
Han, Bo; Mehra, Rohit; Dhanasekaran, Saravana M et al. (2008) A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5-ETV4 fusion protein in prostate cancer. Cancer Res 68:7629-37
Mehra, Rohit; Tomlins, Scott A; Yu, Jianjun et al. (2008) Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res 68:3584-90
Helgeson, Beth E; Tomlins, Scott A; Shah, Nameeta et al. (2008) Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer Res 68:73-80
Kim, Jung H; Dhanasekaran, Saravana M; Mehra, Rohit et al. (2007) Integrative analysis of genomic aberrations associated with prostate cancer progression. Cancer Res 67:8229-39
Taichman, Russel S; Loberg, Robert D; Mehra, Rohit et al. (2007) The evolving biology and treatment of prostate cancer. J Clin Invest 117:2351-61

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