Personalized Therapeutics for Inhibiting Breast Cancer Metastasis

乳腺癌是一个重大的全球健康问题；它是女性中第二常见的癌症

Breast cancer is a major global health issue; it is the second most common form of cancer in women exceeded only by lung cancer. Current breast cancer treatments are regulated by cell surface presentation; for example, breast cancer cells that express estrogen receptor-α (ERα) and human epidermal growth receptor-2 (HER2) on their surface are treated with hormone (anti-estrogen or aromatase inhibitors) or targeted (Herceptin) therapies, respectively. In this proposal, we propose a personalized approach to treat four metastatic breast cancer populations: black, white, over 40 and under 40. These populations were chosen based on statistical differences in survival and rate of diagnoses. I will characterize the surface density and proximity of two Gprotein coupled receptors that facilitate tumor chemotaxis, CXC chemokine receptor type 4 (CXCR4) and CC chemokine receptor type 7 (CCR7). CXCR4 and CCR7 induce directional migration of tumor cells along chemokine gradients in a manner similar to lymphocyte homing. In addition, lipocalin-2 (Lcn2) has been shown to induce the epithelial to mesenchymal transition (EMT). I propose to synthesize complementary engineered liposomes (CELs) that cooperatively bind CXCR4 and CCR7 and deliver short interfering RNA (siRNA) to knockdown Lcn2. Homogeneous and biphasic CELs are designed to complement the relative surface density and organization of receptors on breast cancer cells by allowing conjugated antibodies to rearrange on the surface or clustering antibodies within gel-phase lipid domains. CEL therapies will be designed to enhance cooperative binding to each cell type and be evaluated to reduce cell migration and invasion. Mechanistic studies will complement in vitro studies; the expression of RhoA, Rac1, Erk1, PI3K, E-cadherin, vimentin, and fibronectin will assess the effect of CEL therapy on cell migration, activation, survival, and the EMT. In vivo tumor progression and metastasis will be evaluated after delivery of CEL therapies. This work will demonstrate similarities and differences between 6 different breast cancer cell lines and deliver a platform technology designed specifically to address tumor metastasis. In comparison to the antibody and the antagonist targeted towards CXCR4 in clinical trials, this method has the advantage of localizing within tumors, cooperatively binding multiple chemokine receptors, blocking chemotaxis, delivering Lcn2 siRNA to impede the EMT, and monitoring biodistribution in vivo via the incorporation of a near infrared chromophore. My previous work, targeting cytokine-activated endothelial cells, presents compounding evidence that vehicles that complement the cell surface enhance binding. I propose to use our knowledge and experience in chemical engineering, material science, and nanotechnology to develop therapeutics that will increase breast cancer patient survival by inhibiting tumor progression and metastasis.