Targeting key growth regulatory molecules in cancer cells has now proven to be an effective therapy for many different types of cancer. Disruption of key growth regulatory molecules may function alone or in combination with cytotoxic chemotherapy. In breast cancer, targeting of human epidermal growth factor receptor 2 (HER2) with trastuzumab has been an important advance. Trastuzumab works as a single agent and in combination with cytotoxic chemotherapy in both early stage and advanced breast cancer. Our laboratory, along with many others, has provided preclinical data demonstrating the value of the insulin-like growth factor (IGF) system as a target for cancer therapy. Recently, several drugs have been developed to target the type I IGF receptor (IGF1R) and some are now entering phase II clinical trials. We have shown that IGF1R and its related receptors regulate many aspects of breast cancer biology and signaling through this receptor system is complex. In order to optimize the use of this strategy as a cancer therapy, a deeper understanding of how the IGF system regulates the cancer phenotype must be understood. We hypothesize that a more complete definition of the IGF system signaling components will assist in the clinical development of anti-IGF therapies. To more fully define the IGF signaling system effectors, we propose to: 1) identify the signaling pathways downstream of IGF1R that couple its activation to specific breast cancer phenotypes, 2) determine the role of the insulin receptor (InsR) in breast cancer, and 3) define the mechanisms of resistance to anti-IGF1R therapy. The success of anti-growth factor receptor cancer therapies has established a new paradigm for treatment of malignancy. As anti-IGF system therapies are emerging as cancer treatments, our long term goal is to define the mechanisms of IGF action in cancer cells in order to inform clinical development of these drugs Our previous work has demonstrated that the targeting of the insulin-like growth factor (IGF) system may be used to block growth and spread of cancer cells. This proposal will explore the molecular pathways used by this system to stimulate cancer cells. The long-term goal is to develop better tools to predict which patients will benefit from anti-IGF therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074285-15
Application #
8214706
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Spalholz, Barbara A
Project Start
1998-01-01
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
15
Fiscal Year
2012
Total Cost
$343,381
Indirect Cost
$114,110
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Yang, Yuzhe; Yee, Douglas (2014) IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC-. Cancer Res 74:2295-305
Zhang, Xihong; Diaz, Michael R; Yee, Douglas (2013) Fulvestrant regulates epidermal growth factor (EGF) family ligands to activate EGF receptor (EGFR) signaling in breast cancer cells. Breast Cancer Res Treat 139:351-60
Fagan, Dedra H; Uselman, Ryan R; Sachdev, Deepali et al. (2012) Acquired resistance to tamoxifen is associated with loss of the type I insulin-like growth factor receptor: implications for breast cancer treatment. Cancer Res 72:3372-80
Zeng, Xianke; Zhang, Hua; Oh, Annabell et al. (2012) Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor. Breast Cancer Res Treat 133:117-26
Yee, Douglas (2012) Insulin-like growth factor receptor inhibitors: baby or the bathwater? J Natl Cancer Inst 104:975-81
Potter, David A; Yee, Douglas; Guo, Zhijun et al. (2012) Should diabetic women with breast cancer have their own intervention studies? Endocr Relat Cancer 19:C13-7
Yang, Yuzhe; Yee, Douglas (2012) Targeting insulin and insulin-like growth factor signaling in breast cancer. J Mammary Gland Biol Neoplasia 17:251-61
Becker, Marc A; Ibrahim, Yasir H; Cui, Xiaojiang et al. (2011) The IGF pathway regulates ERα through a S6K1-dependent mechanism in breast cancer cells. Mol Endocrinol 25:516-28

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