The goal of this grant application is to support the development of a mentored-career that focuses on building a foundation of mechanism-based Phase I/II therapeutic trials directed at breast cancer. It is the intent of this application to utilize currently established research relationships, which supports a mentoring environment in the design and administration of Phase I/II trials, and provides background education in the basics of scientific reason. Therapeutic trials will be designed which integrate experts in pharmacokinetic and pharmacodynamic analysis, mechanisms of apoptosis, and angiogenesis, with clinicians specializing in the treatment of breast cancer at the Ireland Cancer Center (ICC) at University Hospitals of Cleveland (UHC) and Case Western Reserve University (CWRU). With the mentoring of Dr. Scot Remick, Director of the Developmental Therapeutics Program, the investigator will test the hypothesis that the therapeutic response of breast cancer to cytotoxic treatment will be enhanced through the addition of novel therapies. Two studies will form the foundation of this hypothesis.
Specific Aim 1 : To enhance the disease-free and overall survival of patients with inflammatory breast cancer receiving doxorubicin with the addition of an angiogenesis inhibitor (SU5416). To determine if there is a correlation between disease response and changes in plasma markers of angiogenesis, tumor microvascular density, and tumor blood flow.
Specific Aim 2 : To enhance the disease response of advanced/metastatic breast cancer and other solid tumors to cisplatin and paclitaxel treatment with the addition of a retinoid, fenretinide (4HPR). To determine if there is a correlation between disease response and changes in tumor tissue retinoid receptor activation and level of apoptosis. This study will also determine if 4-HPR therapy induces in vivo expression of TIG3, a novel gene involved with apoptosis, in treated patients, and confirm that its level of expression correlates with disease response. A Phase II breast cancer trial will follow the completion of this Phase I protocol. These studies will provide a foundation for active participation of collaborative laboratories, resulting in a successful career developing a mechanism-based therapeutic research program in breast cancer.
| Baar, Joseph; Silverman, Paula; Lyons, Janice et al. (2009) A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: impact on angiogenic biomarkers. Clin Cancer Res 15:3583-90 |
| Overmoyer, Beth; Fu, Pingfu; Hoppel, Charles et al. (2007) Inflammatory breast cancer as a model disease to study tumor angiogenesis: results of a phase IB trial of combination SU5416 and doxorubicin. Clin Cancer Res 13:5862-8 |
