Fatty Acid Synthase (FASN) is an enzyme that catalyzes the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA in cells. Normal cells (except liver and adipose tissue) have low levels of FASN activity. In rapidly proliferating cancer cells fatty acids can be synthesized de novo to provide lipids for membrane formation. Our general hypothesis is that FASN is a promising therapeutic target for invasive breast carcinomas. FASN is highly expressed in invasive breast and other carcinomas, and is prominent in higher grade tumors correlating with poor prognosis. Our data shows that 60% of invasive breast carcinomas express high levels of FASN and FASN expression is a marker for poor prognosis and poor disease free survival. Interestingly, FASN is highly coexpressed with the three breast cancer histopathological groups: Estrogen Receptor positive (ER+), HER2 3+ overexpressing (HER2+) and triple negative (TN) [which do not express ER, Progesterone Receptor (PgR), and HER2+). Our preliminary studies show that pharmacological inhibition of FASN in breast cancer synergizes with chemotherapeutical agents such as Taxol, and with antiestrogens and trastuzumab targeted therapies increasing growth inhibition and apoptotic cell death in vitro and in vivo. We demonstrated that blockage of FASN inhibits tumor growth and induces apoptosis, triggering deteriorating effects which lead to apoptotic cell death including: i inhibition of palmitate, hence the inhibition of sphingolipids synthesis;ii) mitochondria damage and release of Cyt c;iii) increase Reactive Oxygen Species (ROS) generation;and iv) upregulation of BH3-only family proteins (Noxa, Bim, Puma). In this proposal we will extend these concepts using a variety of biochemical, genetic and therapeutic approaches: First, we will examine the clinical value of FASN as a theranostic (predictive) marker for response to targeted therapy in breast-cancer patients, in adjuvant and neoadjuvant setting. Second, we will assess the role of: i) BH3-only proteins Noxa, Bim and Puma in FASN inhibition induced apoptosis: ii) the synergistic effect of inhibitors of FASN and Taxol induced apoptosis;iii) the lnk between FASN inhibition and increased ROS production and BH3-only protein upregulation. Last, we will perform preclinical studies to assess a newly develop anti-FASN agent in combination with antiestrogens, Trastuzumab and Taxol. This proposal will provide new insight into the action of FASN inhibitors and the information needed to translate our findings into the clinic. Our goal is to develop novel rationally designed therapeutic approaches for breast cancer.

Public Health Relevance

This application responds to the urgent need to develop strategies to predict response to cancer treatments. The characterization of Fatty Acid Synthase as a molecular event accompanying the pathogenesis and natural history of breast cancer disease will help determine its clinical relevance to metastatic breast cancer patients and will help in the development of effective treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA116623-07A1
Application #
8295514
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Forry, Suzanne L
Project Start
2005-09-16
Project End
2015-06-30
Budget Start
2012-08-10
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$461,186
Indirect Cost
$171,132
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Lupu, Ruth; Colomer, Ramon; Menendez, Javier A (2008) An easy, rapid and objective mathematical method to identify fatty acid synthase (oncogenic antigen-519) modulators with potential anticancer value. Clin Transl Oncol 10:219-26
Menendez, Javier A; Lupu, Ruth (2007) Transphosphorylation of kinase-dead HER3 and breast cancer progression: a new standpoint or an old concept revisited? Breast Cancer Res 9:111
Menendez, Javier A; Lupu, Ruth (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7:763-77
Menendez, Javier A; Lupu, Ruth (2006) Oncogenic properties of the endogenous fatty acid metabolism: molecular pathology of fatty acid synthase in cancer cells. Curr Opin Clin Nutr Metab Care 9:346-57
Lupu, Ruth; Menendez, Javier A (2006) Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators? Endocrinology 147:4056-66
Menendez, Javier A; Lupu, Ruth (2006) Mediterranean dietary traditions for the molecular treatment of human cancer: anti-oncogenic actions of the main olive oil's monounsaturated fatty acid oleic acid (18:1n-9). Curr Pharm Biotechnol 7:495-502
Lupu, Ruth; Menendez, Javier A (2006) Pharmacological inhibitors of Fatty Acid Synthase (FASN)--catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? Curr Pharm Biotechnol 7:483-93
Menendez, Javier A; Vazquez-Martin, Alejandro; Ropero, Santiago et al. (2006) HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated fatty acid, alpha-linolenic acid (ALA; 18:3n-3), in breast cancer cells: the "fat features" of the "Mediterranean diet" as an "anti-HER2 cocktail". Clin Transl Oncol 8:812-20