Among the most promising novel biological agents are the epidermal growth factor receptor family inhibitors. Although a Phase III randomized trial recently proved that EGFR inhibitors are effective radiosensitizers, the clinical experience of several non-radiosensitization trials show disappointing low response rates. The discordance between strongly positive preclinical and modest clinical outcomes maybe due to the relatively poor ability to select tumors amenable to EGFR inhibitor therapy. In our breast cancer cell line radiosensitization studies using a dual EGFR/HER2 inhibitor, GW572016, we found that inhibition of downstream signaling corresponded with response, but inhibition of receptor phosphorylation did not. Our hypothesis is that response to EGFR/HER2 inhibitors will depend not only on inhibition of the receptor, but also on effective inhibition of the downstream signals (MARK, PI3K, or STAT cascades) that drive radiation response, and that tumors in which MARK, PI3K, or STAT activation is not dependent on EGFR/HER2 will not be radiosensitized. Since cell lines and xenografts derived from cell lines poorly represent the heterogeneity of clinical tumors, we will test our hypothesis in tumors derived from patients, both in the context of a treatment trial and in tumors transplanted directly from patients to mice.
In Specific Aim 1, we will determine the signaling pathways involved in GW573016 radiosensitization.
In Specific Aim 2, we will determine mechanisms of resistance to radiosensitization.
In Specific Aim 3, we will determine whether inhibition of downstream signaling predicts response to GW572016. Our results will show which EGFR/HER2 signals are responsible for breast cancer radiation response, identifying biomarkers to select patients whose breast cancer is likely to respond to EGFR/HER2 inhibitors, improving outcome and avoiding ineffective treatment. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115888-03
Application #
7477312
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Stone, Helen B
Project Start
2006-09-21
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$184,888
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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