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Understanding and Improving the Effectiveness of Trastuzumab-Based Therapy for Breast Cancer
Tumor Cell Biology IV
Trastuzumab, a humanized monoclonal antibody targeting the HER2/neu protein, has been shown to be an efficacious treatment for HER2-overexpressing metastatic breast cancer. When used in combination with chemotherapy, overall response rates greater than 50% have been reported. However, the majority of cases represent partial rather than complete responses, and overall survival is increased only 4-5 months compared to standard chemotherapy alone, indicating that current therapies are rarely curative. Our goal is to identify novel protein kinases or cellular pathways that modulate the sensitivity of breast cancer cells to trastuzumab treatment. These studies will identify novel therapeutic targets for treatment of HER2-overexpressing breast cancer, and will also provide insight into potential mechanisms of trastuzumab resistance in patients that do not respond to therapy. The molecular mechanisms underlying trastuzumab sensitivity and resistance are poorly understood. We therefore propose to take an unbiased and systematic approach to identify cellular proteins and pathways that modulate trastuzumab sensitivity. In breast cancer cell lines that overexpress HER2, trastuzumab treatment results in a cytostatic response, decreasing cell proliferation by approximately 40%. Thus, even in vitro , the effects of trastuzumab on cell proliferation are incomplete. We propose to exploit this incomplete inhibition of cell growth and failure to induce apoptosis to identify specific kinases and/or small molecules that convert the partial trastuzumab-mediated cytostatic arrest into a complete arrest or to an apoptotic response. In our first aim, we will screen an siRNA library, targeting all human protein kinases, for siRNAs that enhance or suppress the sensitivity of breast cancer cells to trastuzumab treatment. In our second aim, we will perform a chemical genetic screen to identify small molecules that enhance or suppress sensitivity of breast cancer cells to trastuzumab. This screen will include compounds of known mechanism of action and also FDA-approved therapeutics to facilitate a rapid progression to xenograft experiments and clinical trials. These unbiased and complementary approaches will provide novel insights into the pathways that mediate trastuzumab sensitivity in HER2-overexpressing cells, and may lead directly to the identification of novel targets or compounds that can be used to enhance the effectiveness of trastuzumab therapy in the clinic.
Researchers are now beginning to understand the molecular causes of breast cancer. Recently this knowledge has been applied to develop a new therapy that inhibits the division of breast cancer cells without harming normal cells. In about 20-30% of breast cancer patients, tumor cells make too much of a protein called HER2. This protein normally regulates the division of many cell types in the body, but when breast cancer cells make too much of this protein, cell division becomes uncontrolled, contributing to tumor development. Unfortunately, patients whose tumors make high levels HER2 often have more aggressive disease than patients whose tumors make normal (low) levels of HER2. However, a new therapy, called trastuzumab (or herceptin), specifically inhibits the division of cells that make too much HER2. Clinical trials have established that trastuzumab, when combined with conventional chemotherapy, can extend the survival of patients with metastatic breast cancer. However, this therapy is not curative in most patients, and some patients do not respond at all to trastuzumab treatment. The goal of this research project is to understand why trastuzumab therapy does not always work, and to identify new ways to improve this therapy. Our research will take advantage of the fact that when breast cancer cells are treated with trastuzumab in culture dishes, its effects are incomplete. Our goal is to identify new ways to convert these partial responses to full responses, so that cell division is completely inhibited in cells treated with trastuzumab. We will also search for ways to induce self-destruction of cells treated with trastuzumab. We will first reduce the level of all human protein kinases in breast cancer cells, one-by-one, and determine how this affects sensitivity of cells to trastuzumab. This approach will identify proteins that might make good targets for new drugs that would enhance trastuzumab therapy. In addition, we will screen collections of chemical compounds and FDA-approved drugs for agents that improve the ability of trastuzumab to inhibit breast cancer cell growth. Together these approaches will help us better understand the cellular pathways that regulate how cells respond to trastuzumab. Furthermore, our study will identify new therapeutic targets or known drugs that can improve the effectiveness of trastuzumab in the clinic.