Obese women clearly are at increased risk for developing endometrial cancer. Numerous epidemiologic studies have demonstrated that obesity is strongly associated with an increased risk of endometrial cancer. While an average woman has a 3% lifetime risk of endometrial cancer, obese women have a 9-10% lifetime risk of endometrial cancer. In a review of diet and cancer by the American Institute for Cancer Research and World Cancer Research Fund (WCRF), authors stated that the evidence relating body mass index and cancer is strongest for endometrial cancer. While excessive production of extragonadal estrogens (estrone) in the adipose tissue of obese women is presumed to be the major contributor to the risk of endometrial cancer, increased serum estrogen levels alone are unlikely to fully account for this effect. Studies by our group and others suggest that insulin resistance associated with obesity contributes to the increased risk of endometrial cancer. In addition, data from our previous funding period suggest that other mechanisms are involved in activating pro-proliferative signaling pathways in the obese endometrium. For the current proposal, our central hypothesis is that metformin can decrease endometrial hyperproliferation and can act as a chemopreventive agent in insulin-resistant obese women. Our three specific aims are 1) to test the hypothesis that metformin can reverse the estrogen-dependent hyperproliferation in the endometrium in an animal model of obesity- induced insulin-resistance, 2) to study novel mechanisms related to the use of metformin for the prevention of endometrial cancer. More specifically, we will examine the hypothesis that adipokines expressed in adipose tissue regulate endometrial proliferation via adipokine receptors, and metformin treatment can prevent this proliferation, and 3) to assess the ability of metformin to modulate surrogate endometrial biomarkers in a cohort of obese, insulin resistant women. It is the goal of this Project to develop novel strategies for the chemoprevention of endometrial cancer in obese, insulin resistant women, a high risk cohort.

Public Health Relevance

The long term goal of this Project is to develop novel strategies for the chemoprevention of endometrial cancer in obese, insulin-resistant women, a high risk cohort. A clinical prevention trial will examine whether metformin, a widely used drug for insulin resistance and diabetes, can potentially prevent endometrial hyperplasia and cancer. Studies that seek to understand the fundamental changes in the endometrium of obese versus lean women will also be performed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA098258-09
Application #
8521097
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$186,431
Indirect Cost
$71,352
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Rupaimoole, Rajesha; Calin, George A; Lopez-Berestein, Gabriel et al. (2016) miRNA Deregulation in Cancer Cells and the Tumor Microenvironment. Cancer Discov 6:235-46
Srivastava, Akhil; Babu, Anish; Filant, Justyna et al. (2016) Exploitation of Exosomes as Nanocarriers for Gene-, Chemo-, and Immune-Therapy of Cancer. J Biomed Nanotechnol 12:1159-73
Yuan, Ying; Hess, Kenneth R; Hilsenbeck, Susan G et al. (2016) Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res 22:4291-301
Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila et al. (2016) FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal. J Clin Invest 126:1885-96
Westin, Shannon N; Sun, Charlotte C; Tung, Celestine S et al. (2016) Survivors of gynecologic malignancies: impact of treatment on health and well-being. J Cancer Surviv 10:261-70
McCampbell, A S; Mittelstadt, M L; Dere, R et al. (2016) Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity. Curr Mol Med 16:252-65
Guo, Beibei; Li, Yisheng; Yuan, Ying (2016) A dose-schedule finding design for phase I-II clinical trials. J R Stat Soc Ser C Appl Stat 65:259-272
Liu, Joyce; Westin, Shannon N (2016) Rational selection of biomarker driven therapies for gynecologic cancers: The more we know, the more we know we don't know. Gynecol Oncol 141:65-71
Wang, Chao; Zhu, Xiaoyong; Feng, Weiwei et al. (2016) Verteporfin inhibits YAP function through up-regulating 14-3-3σ sequestering YAP in the cytoplasm. Am J Cancer Res 6:27-37
Chen, Tenghui; Wang, Zixing; Zhou, Wanding et al. (2016) Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types. BMC Genomics 17 Suppl 2:394

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