Breast cancer is the most frequently diagnosed cancer and one of the leading causes of cancer related death in women. About 80-85% of all breast cancers have expressed estrogen receptor (ER), progesterone receptor (PR), or hormone epidermal growth factor receptor 2 (HER-2). These ER, PR and HER-2 receptors enable targeted treatment by designing therapeutics that can recognize these receptors. One small subtype, which do not express ER, PR and HER-2 and lack all three receptors, is called Triple negative breast cancer (TNBC). TNBC represents about 10-15% of all breast cancers. The vast majority of therapies targeting these receptors cannot be used for treating TNBC in clinic. Compared to other breast cancers that can be effectively treated by hormonal therapies or HER-2 targeted therapies, TNBC has a much lower survival rate, and is more likely to recur after treatment and to spread beyond the breast. Current treatment of TNBC in clinic has been largely limited to regimens based on conventional small molecule chemotherapeutic agents, such as paclitaxel. In fact, paclitaxel has been used as a first-line treatment for TNBC and is recommended for all lines of therapy to breast cancer. However, like many small molecule chemotherapeutics, paclitaxel has short circulation half-life and very poor penetration and retention capability in solid tumors. A paclitaxel formulation with more sustained availability and improved penetration in the tumors of TNBC may result in more effective treatment. The goal of this R01 project is to develop paclitaxel-silica nanoparticles, a class of size precisely controlled nanomedicine that may treat TNBC more effectively than paclitaxel. We will first explore the controlled synthesis of these nanomedicine, identify size range and surface property for optimal treatment of TNBC. We will then use three representative TNBCs, the MDA-MB-231 orthotopic model, the 4T1 metastatic TNBC model and the patient derived xenograft model, for complete evaluation of the therapeutics efficacy of paclitaxel-silica nanoparticle. Finally, we will address safety issue of the nanomedicine and explore the molecular and pathological mechanisms of nanomedicine in treating TNBCs.
Triple negative breast cancer is a very aggressive, low-survival breast cancer and cannot be treated by routinely used drugs in clinic because of lacking critical receptors that enable the recognition by these drugs. In this R01 proposed study, we aim to develop paclitaxel-silica nanoparticles, a class of size precisely controlled nanomedicine, for effective treatment of triple negative breast cancer.
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