Obesity is a public health problem globally, and two-thirds of US men are overweight or obese. For prostate cancer patients, the obesity epidemic is of concern since men who are overweight before or at the time of diagnosis are at increased risk of biochemical recurrence and cancer-specific mortality. There are several outstanding questions underlying the association between obesity and lethal prostate cancer whose answers are needed to shed light on the translational potential among prostate cancer patients. Our study aims to elucidate mechanisms underlying the link between obesity and lethal prostate cancer and identify patient subgroups more susceptible to the obesity milieu. We hypothesize that obesity may act through local tumor effects which are We hypothesize that obesity may act through local tumor effects which are """"""""the seed"""""""" to increase a prostate cancer's lethal potential as well as via systemic effects that fuel """"""""the soil"""""""" for metastatic growrth. We focus on metabolism and inflammation pathways - two domains with established links to obesityand investigate biomarkers iri locally in prostate tissue as well as in circulation. Moreover, we employ a discovery-based aim in tumors to identify novel pathways enriched in the tumors of prostate cancer patients who are overweight and develop lethal cancer, and endeavor that may unveil new opportunities for secondary prevention. Our population-based study of obesity and lethal prostate cancer is nested among men with incident prostate cancer who were participants within the DF/HCG SPORE in Prostate Gancer biorepository for whom prostate tissue and blood specimens are available, and uniquely focuses on lethal cancer as the primary endpoint. Obesity represents a means to discover drivers of lethal prostate cancer, as well as being a modifiable risk factor in secondary prevention. Weight loss is challenging, and thus identifying specific pathways in tumors and in circulation most strongly underlying the obesity-lethal prostate cancer link is critical to inform on optimal prevention strategies. The translational goals ofthe project are the identification of patients at high risk of the consequences of obesity in order to inform the design of randomized trials and augment the success of secondary prevention strategies. The work will lead to a detailed understanding of the effect of prostatic and systemic drivers of obesity on lethal prostate cancer, an endeavor that will strengthen causality of the association.

Public Health Relevance

Prevention of lethal prostate cancer is a pressing public health issue. Given the high prevalence of obesity among men in the US and globally, obesity is a potentially important modifiable factor for lethal disease among prostate cancer patients. This project aims to elucidate the key pathways in tumors and in circulation in order to inform about secondary prevention and identify subgroups of prostate cancer patients at the greatest risk of the consequences of obesity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA090381-12
Application #
8764821
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
Pakula, Hubert; Linn, Douglas E; Schmidt, Daniel R et al. (2018) Protocols for Studies on TMPRSS2/ERG in Prostate Cancer. Methods Mol Biol 1786:131-151
Elfandy, Habiba; Armenia, Joshua; Pederzoli, Filippo et al. (2018) Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate. Mol Cancer Res :
Han, W; Gao, S; Barrett, D et al. (2018) Reactivation of androgen receptor-regulated lipid biosynthesis drives the progression of castration-resistant prostate cancer. Oncogene 37:710-721
Stopsack, Konrad H; Gonzalez-Feliciano, Amparo G; Peisch, Samuel F et al. (2018) A Prospective Study of Aspirin Use and Prostate Cancer Risk by TMPRSS2:ERG Status. Cancer Epidemiol Biomarkers Prev 27:1231-1233
Russo, Joshua W; Liu, Xiaming; Ye, Huihui et al. (2018) Phosphorylation of androgen receptor serine 81 is associated with its reactivation in castration-resistant prostate cancer. Cancer Lett 438:97-104
Pettersson, Andreas; Gerke, Travis; Penney, Kathryn L et al. (2018) MYC Overexpression at the Protein and mRNA Level and Cancer Outcomes among Men Treated with Radical Prostatectomy for Prostate Cancer. Cancer Epidemiol Biomarkers Prev 27:201-207
Tsang, Sabrina H; Peisch, Samuel F; Rowan, Brendan et al. (2018) Association between Trichomonas vaginalis and prostate cancer mortality. Int J Cancer :
Arai, Seiji; Jonas, Oliver; Whitman, Matthew A et al. (2018) Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis. Clin Cancer Res 24:5458-5470
Francini, Edoardo; Gray, Kathryn P; Xie, Wanling et al. (2018) Time of metastatic disease presentation and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC). Prostate 78:889-895
Russo, Joshua W; Gao, Ce; Bhasin, Swati S et al. (2018) Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer. Cancer Res 78:6354-6362

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