BME PhD Candidate Megan Ngoc Dang will be defending her dissertation:


Nanoparticle-Mediated Delivery of Antibodies and/or RNA for Gene Regulation in Triple-Negative Breast Cancer



Triple-negative breast cancer (TNBC) is an aggressive disease that is unsusceptible to most current targeted or hormonal therapies because it lacks expression of the three receptors, estrogen, progesterone, and human epidermal growth factor 2 receptors. Consequently, patients with TNBC suffer from earlier relapse, increased rates of metastasis, and lower survival rates than patients with other forms of breast cancer. New treatment strategies must be developed to improve the prognosis for TNBC patients, and the research proposed here seeks to meet this need through targeting alternative TNBC signaling pathways. The progression of TNBC is driven through aberrantly expressed pathways that transcribe for downstream oncogenic genes. Subsequently, the ability to regulate the expression of such specific genes implicated in tumor progression is a promising strategy to combat TNBC. Two targets of interest are miR-34a and the Wnt signaling pathway. Several studies have shown that miRNA miR-34a is downregulated in TNBC, and its loss of expression correlates with the dysregulation of tumor suppressive genes and ultimately with poorer clinical outcomes. Likewise, Wnt signaling is hyperactive in TNBC cells and is characterized by the dysregulation of β-catenin proteins, which leads to the translation of overexpressed oncogenes. The delivery of RNA therapeutics, either by miRNA restoration or siRNA silencing, would regulate either miR-34a or the Wnt signaling pathway through the RNA interference (RNAi) mechanism. However, prior research has shown that naked RNA delivery is limited therapeutically because, like other nucleic acids, they are unstable in biological fluids, exhibit unfavorable pharmacokinetics, and cannot passively enter cells. To overcome these issues, various nanocarriers have been designed to protect RNAs and other nucleic acids from degradation and deliver them into target cells to initiate gene regulation. The biggest limitation of these systems is that they lack specificity or either targeting agents or release mechanisms. This dissertation will address these needs by developing two different NP platforms that can suppress the expression of genes known to drive TNBC progression via antibody and/or RNA delivery through three main aims: (1) Assess photoresponsive miR-34a/NS conjugates for light-triggered gene regulation of TNBC; (2) Examine the effect of Wnt inhibitory antibody/siRNA nanocarriers against TNBC in vitro; and (3) Evaluate the use of Wnt inhibitory NPs to reduce primary tumor growth in vivo. This research is both innovative and impactful because it will develop and validate two distinct nanocarrier platforms to treat TNBC through gene regulation. These systems will utilize either photoactivation or antibody targeting to enable high precision therapy of TNBC. Future research will expand this work in further improving the delivery of RNA therapeutics to maximize the impact on the targeted TNBC signaling pathways.