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    Research Grants Awarded

    An Integrated Approach to Biomarker Validation in Patients with HER-2 Positive Metastatic Breast Cancer Treated with Rapamycin and Trastuzumab

    Study Section:
    Tumor Cell Biology IV

    Scientific Abstract:
    The response rates of patients with HER-2 positive metastatic breast cancer to single agent trastuzumab (Hereceptin) is 12-26%, and when combined with cytotoxic chemotherapy the response rate is as high as 80%. However, a significant percentage of patients who initially respond to Herceptin will acquire resistance. Preclinical studies suggest that therapies targeting PI3K/Akt/mTOR pathway might overcome resistance to Herceptin. We propose to evaluate pre and post therapy changes in the levels, phosphorylation status and/or subcellular localization of HER2, Akt, S6K and 4EBP1 in blood and tumor tissues of HER2 positive metastatic breast cancer patients treated with the novel combination of Herceptin and Rapamycin, a specific antagonist of mTOR (mammalian Target Of Rapamycin), after progression on prior Herceptin therapy. We also propose to test if currently available RNA expression profiles associated with response to Herceptin will be predictably altered in tumors treated with this novel combination. In addition, the PI3K/Akt/mTOR pathway plays a central role in cellular detection of nutrients and is involved in the regulation of cellular glucose. Therefore, the use of the imaging modality fluordeoxyglucose (FDG)-PET provides a unique opportunity to measure the activity of the mTOR inihibitor, Rapamycin in tumor tissue. We propose to measure uptake of glucose with FDG-PET before and after one week of Rapamycin therapy on this clinical trial, and correlate this with mTOR inhibition in target tissue. If the combination of Rapamycin and Herceptin proves to be active in HER2 positive metastatic breast cancer patients, then further evaluation of this combination in early stages of breast cancer is warranted in both the adjuvant and neoadjuvant settings. In addition, data collected from the correlative studies in this trial may aid in patient selection for future clinical trials.

    Lay Abstract:
    Herceptin is a therapy proven to prolong survival of breast cancer patients with tumors that have high levels of a protein called HER2. A significant number of patients, who initially respond to Herceptin, will develop resistance to the drug. We are conducting a clinical trial to study the activity of a drug called Rapamycin in overcoming resistance to Herceptin in patients who previously progressed on Herceptin therapy. We propose to study the presence and activity of specific proteins and genes in blood and tissue of patients on this trial, as biomarkers to predict response to this novel drug combination. In addition, we propose to evaluate the use of Positron Emission Tomography (also known as a PET scan), a diagnostic examination used most often to detect cancer and to examine the effects of cancer therapy by characterizing biochemical changes in the cancer, as a method of detecting early response to this drug combination. If the combination of Rapamycin and Herceptin proves to be active in metastatic breast cancer patients with tumors that have high levels of HER2, then further evaluation of this combination in early stages of breast cancer is warranted. In addition, data collected from the laboratory studies in this trial may aid in patient selection for future clinical trials.