Although great strides have been made in the treatment and cure of early stage breast cancer, metastatic breast cancer remains incurable, accounting for more than 40,000 deaths in the United States alone. Approximately 25% of breast cancers have been found to overexpress the Her-2/neu protein, a member of the Epidermal Growth Factor Receptor family. Patients with Her-2/neu breast cancers experience a more aggressive clinical course. Trastuzumab (Herceptin), a monoclonal antibody targeting the Her-2/neu protein, improves overall survival in patients with metastatic Her-2/neu overexpressing breast cancer and reduces the recurrence of disease by as much as 50% in high-risk settings. Despite this progress, trastuzumab resistant tumors have emerged, resulting in incurable disease. Suberoylanilide Hydroxamic Acid (SAHA), a histone deacetylase inhibitor, enhances gene expression of pro-death molecules in cancer cells and overcomes trastuzumab resistance in the laboratory. A cooperative group clinical trial of the combination of SAHA and trastuzumab will target these patients with Her-2/neu overexpressing breast cancer previously resistant to single agent trastuzumab. Several new non-cytotoxic agents, such as SAHA and trastuzumab, specifically target tumor cell biological processes or elements of the tumor stroma. In many cases, the appropriate doses of such """"""""biologic agents"""""""" will not be maximally tolerated, but rather will be the lowest doses found to selectively and thoroughly inhibit the function of their target(s). Accordingly, it is desirable to have direct access to relevant target cells in order to learn about a drug's mechanism of action and its pharmacodynamic or pharmacogenomic properties. Despite much effort, it has proven difficult to directly sample solid tumor masses even once in the context of early-phase clinical trials. Using an immunomagnetic nanoparticle cell capture system, we have previously isolated and enumerated circulating tumor cells (CTC) in cancer patients. These studies demonstrated that circulating epithelial tumor cells can be isolated and enumerated in sufficient numbers to permit analysis of apoptosis and cellular phenotype(s). Based on this emerging technology, we will isolate circulating tumor cells from the peripheral blood of treated patients in this trial to determine if treatment- induced changes in the molecular characteristics of these tumor cells relate to the clinical outcomes of patients participating in this clinical trial. We believe this approach can provide important insights into how these newer biologic agents work, and also will provide an important new approach to assist in the development of new treatments for cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA121541-01
Application #
7111325
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Xie, Heng
Project Start
2006-07-07
Project End
2008-06-30
Budget Start
2006-07-07
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$273,173
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111