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)
Type
Research Project (R01)
Project #
2R01CA131945-06A1
Application #
8761515
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mohla, Suresh
Project Start
Project End
Budget Start
Budget End
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
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