Clinicians and researchers are currently unable to distinguish at diagnosis with sufficient confidence men with indolent prostate cancer (CaP) from those who have aggressive disease. At present, the strongest predictor of lethal CaP is Gleason score. Utilizing gene expression array data, we previously identified a 157 gene mRNA signature that distinguished high from low Gleason score. This signature significantly improved prediction of lethal disease among men with clinically heterogeneous Gleason score 7. The signature may have clinical utility, but before applying it to patients it must be further refined and then tested in biopsy specimens to determine if the predictive accuracy is sufficient to influence treatment decisions at the time of diagnosis. This mRNA study also identified metabolic pathways differentially enriched in high and low grade disease, generating hypotheses for biological mechanisms that may underlie CaP differentiation and clinical progression. Since different types of biological data may add to the mRNA signature as well as provide different biological information, it is worthwhile to further investigate the metabolic pathways identified. We therefore propose to build upon our promising expression profiling findings with the following Specific Aims: 1) Preparation and testing of Gleason signature of lethal disease for clinical use -To determine if the mRNA signature can be applied in the clinic, we will further validate it by testing its predictive accuracy in biopsy specimens at the time of diagnosis. We hypothesize that within Gleason score 7, the signature's ability to predict lethal disease may improve if applied specifically to the grade 3 or grade 4 focus of the tumor 2) Metabolomics bf Gleason grade In tumor as predictor of lethal disease - Our mRNA study identified metabolic pathways (pyrimidine, propanoate, and beta-alanine metabolism) differentially enriched in high and low grade tumors. Our preliminary data suggests these same pathways may be differentially enriched using metabolomic data;we hypothesize that metabolites may themselves be associated with Gleason score and lethal disease. 3) Metabolomics of Gleason grade in serum as biomarker for upgrading - We hypothesize that metabolites in serum associated with Gleason grade may indicate the presence of higher-grade tumor not detected at biopsy and could serve as a biomarker for monitoring disease progression of active surveillance patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA090381-12
Application #
8764822
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Dickerman, Barbra A; Ahearn, Thomas U; Giovannucci, Edward et al. (2017) Weight change, obesity and risk of prostate cancer progression among men with clinically localized prostate cancer. Int J Cancer 141:933-944
Cacciatore, Stefano; Zadra, Giorgia; Bango, Clyde et al. (2017) Metabolic Profiling in Formalin-Fixed and Paraffin-Embedded Prostate Cancer Tissues. Mol Cancer Res 15:439-447
Sinnott, Jennifer A; Peisch, Sam F; Tyekucheva, Svitlana et al. (2017) Prognostic Utility of a New mRNA Expression Signature of Gleason Score. Clin Cancer Res 23:81-87
Zareba, Piotr; Flavin, Richard; Isikbay, Masis et al. (2017) Perineural Invasion and Risk of Lethal Prostate Cancer. Cancer Epidemiol Biomarkers Prev 26:719-726
Han, W; Gao, S; Barrett, D et al. (2017) Reactivation of androgen receptor-regulated lipid biosynthesis drives the progression of castration-resistant prostate cancer. Oncogene :
McKay, Rana R; Werner, Lillian; Mostaghel, Elahe A et al. (2017) A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 23:935-945
Qu, Fangfang; Xie, Wanling; Nakabayashi, Mari et al. (2017) Association of AR-V7 and Prostate-Specific Antigen RNA Levels in Blood with Efficacy of Abiraterone Acetate and Enzalutamide Treatment in Men with Prostate Cancer. Clin Cancer Res 23:726-734
Graff, Rebecca E; Ahearn, Thomas U; Pettersson, Andreas et al. (2017) Height, obesity, and the risk of TMPRSS2:ERG-defined prostate cancer. Cancer Epidemiol Biomarkers Prev :
Liu, Xiaming; Gao, Yanfei; Ye, HuiHui et al. (2017) Positive feedback loop mediated by protein phosphatase 1? mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer. Nucleic Acids Res 45:3738-3751
Tyekucheva, Svitlana; Bowden, Michaela; Bango, Clyde et al. (2017) Stromal and epithelial transcriptional map of initiation progression and metastatic potential of human prostate cancer. Nat Commun 8:420

Showing the most recent 10 out of 240 publications