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    Research Grants Awarded

    The Role of Therapy-Induced Autophagy and Apoptosis in Metastatic Breast Cancer Response

    Study Section:

    Scientific Abstract:
    Women with metastatic breast cancer need more effective therapy. Thermal therapy may increase treatment response and survival. Also, a rapid validation of response could speed new therapy development and permit personalization of therapy. We hypothesize that two types of tumor cell death, autophagy and apoptosis, are key to therapy response, and that detection of protein biomarkers of these cell death pathways, and their associated immune responses in plasma, saliva, and tumor tissue of responders shortly after therapy may signal response. We plan therefore to (i) use a highly promising novel treatment of fever-range thermal therapy (FR-TT) carefully scheduled to enhance chemotherapy of oxaliplatin (Eloxatin) in a syngeneic rat model of metastatic breast cancer, and (ii) measure selected proteins specifically involved in tumor autophagy, apoptosis, and associated immune presentation in blood, saliva and tumor tissue before and after treatment. We theorize this will allow us to determine whether these proteins predict treatment response. Autophagy, apoptosis, and immunological response in plasma, saliva, and tumor will be measured by Western blot analysis. Tumor autophagy, apoptosis, and immunological response will be analyzed by RNA microarray, as well as standard and electron microscopy. Tumor apoptosis will be also be measured by TUNEL assay. We present preliminary data supporting the effectiveness of our treatment. Combining a novel therapeutic regimen with novel examination of biomarkers of autophagy, apoptosis and immunological response along with our successful track record in translating novel thermo-chemotherapies from rat cancer models into the clinic uniquely positions us to perform the proposed research. By focusing on the role of treatment-induced autophagy, apoptosis and immune response, we hope to develop effective, individualized therapy for metastatic breast cancer and significantly increase patient survival.

    Lay Abstract:
    Patients suffering from metastatic breast cancer need better therapy. If one could predict before, or very soon after, the start of therapy whether a patient will respond to treatment, treatment could be personalized for the person and their survival would improve. We propose that two types of cancer cell death, autophagy and apoptosis, are key to tumor response to therapy, and that markers of the two types of cell death (autophagy and apoptosis) will be prognostic of response to treatment. To test this theory, however, a more powerful therapy is required. We therefore plan to optimize a highly promising novel treatment of fever-range thermal therapy (FR-TT), carefully scheduled to enhance chemotherapy of oxaliplatin in a rat model of metastatic breast cancer. Using state-of?the-art methods measuring protein substances seen in cell death before, and soon after, beginning treatment in blood, saliva and cancer tissue, we aim to (i) help explain how FR-TT enhances chemotherapy, and (ii) see if these protein substances predict treatment response. We may also detect proteins produced by the immune system in response to these cell death pathways. Standard ways to analyze cells will further show the contributions of autophagy and apoptosis to tumor response. Our preliminary data attests to the power and effectiveness of our treatment, and shows that autophagy may be a part of tumor cell death following successful therapy. Our long track-record of translating innovative, effective, treatments from our laboratory to the clinic, promises to improve patient survival from metastatic breast cancer.