Prostate cancer (PCa) arising in overweight or obese patients is associated with higher mortality. The molecular underpinnings of the relationship between systemic metabolic alterations and biologically aggressive PCa, however, are poorly understood. The metabolic syndrome (MetS) is characterized clinically by the combination of metabolic alterations including dyslipidemia, insulin resistance and central obesity, and biochemically by inactivation of the energy sensor 5'AMP-activated protein kinase (AMPK), principally in liver and muscle. We hypothesize that PCa arising in patients with MetS is characterized by a unique molecular phenotype driven by the inactivation of AMPK in prostate tumor cells. We showed that MetS is a risk factor for aggressive prostate cancer. Epidemiological studies have reported reduced cancer risks and cancer related mortality in diabetics using the indirect AMPK activator metformin. In addition, we determined that direct AMPK activation inhibits PCa cell growth in vitro and in vivo via the suppression of de novo lipogenesis and to a lesser extent of the mTORC1 pathway. We plan to dissect the molecular pathways that link systemic biochemical alterations of MetS to AMPK inactivation in prostate tumors. We are looking to see if MetS, or a genetic predisposition to MetS, leads to a unique molecular phenotype in PCa tumors. The ultimate goal is to identify PCa patients that might benefit from therapeutic targeting of AMPK or its downstream effector pathways, which include but may not be limited to mTOR and protein synthesis and lipogenesis. In order to accomplish this, we propose to use a multi-disciplinary approach that includes mouse genetics, cellular biology, biochemistry, bioinformatics and molecular epidemiology, with the following specific aims:
Aim 1. To investigate the role of AMPK in prostate cancer onset and progression in genetically engineered cells and mouse models;
Aim 2. To develop molecular signatures of AMPK inactivation and study their relationship with the metabolic syndrome in a human population;
Aim 3. To explore the genetic mechanism linking prostate cancer to diabetes/metabolic syndrome;
and Aim 4. To evaluate the potential of the AMPK inactivation signature in selection of therapeutics utilizing ex-vivo organotypic slice cultures of human prostate cancer. This project will establish a molecular connection between MetS and the aggressive form of PCa that arises in these individuals, and provide a biomarker for the identification of PCa with AMPK inactivation. These patients, over-represented in the African-American population, will likely benefit from novel therapeutics strategies directed at metabolic targets.

Public Health Relevance

Prostate cancer arising in patients who are obese or have the metabolic syndrome is associated with higher mortality. Certain populations, such as African Americans, are both more prone to develop MetS and are known to have more aggressive prostate cancer. We hypothesize that a subset of prostate cancer patients has tumors characterized by a metabolic phenotype driven by the inactivation of the genetic regulator of energy balance (AMPK) in tumor cells. This project will establish a molecular connection between the metabolic syndrome, AMPK, and aggressive prostate cancer, providing a novel biomarker for the identification of patients with this metabolic subtype who will likely benefit from novel therapeutics strategies directed at metabolic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA131945-06A1
Application #
8761515
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mohla, Suresh
Project Start
2007-12-01
Project End
2019-06-30
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
6
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
Kenfield, Stacey A; Batista, Julie L; Jahn, Jaquelyn L et al. (2016) Development and Application of a Lifestyle Score for Prevention of Lethal Prostate Cancer. J Natl Cancer Inst 108:
Yang, Meng; Ayuningtyas, Azalea; Kenfield, Stacey A et al. (2016) Blood fatty acid patterns are associated with prostate cancer risk in a prospective nested case-control study. Cancer Causes Control 27:1153-61
Yang, Meng; Sesso, Howard D; Colditz, Graham A et al. (2016) Effect Modification by Time Since Blood Draw on the Association Between Circulating Fatty Acids and Prostate Cancer Risk. J Natl Cancer Inst 108:
Sinnott, Jennifer A; Peisch, Sam; Tyekucheva, Svitlana et al. (2016) Prognostic Utility of a New mRNA Expression Signature of Gleason Score. Clin Cancer Res :
Cacciatore, Stefano; Loda, Massimo (2015) Innovation in metabolomics to improve personalized healthcare. Ann N Y Acad Sci 1346:57-62
Tyekucheva, Svitlana; Martin, Neil E; Stack, Edward C et al. (2015) Comparing Platforms for Messenger RNA Expression Profiling of Archival Formalin-Fixed, Paraffin-Embedded Tissues. J Mol Diagn 17:374-81
Zadra, Giorgia; Batista, Julie L; Loda, Massimo (2015) Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies. Mol Cancer Res 13:1059-72
Hoffmann, Thomas J; Van Den Eeden, Stephen K; Sakoda, Lori C et al. (2015) A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences. Cancer Discov 5:878-91
Martin, Neil E; Gerke, Travis; Sinnott, Jennifer A et al. (2015) Measuring PI3K Activation: Clinicopathologic, Immunohistochemical, and RNA Expression Analysis in Prostate Cancer. Mol Cancer Res 13:1431-40
Yang, Meng; Kenfield, Stacey A; Van Blarigan, Erin L et al. (2015) Dairy intake after prostate cancer diagnosis in relation to disease-specific and total mortality. Int J Cancer 137:2462-9

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