Molecular Medicine 2018
Area of Doctoral Study: Molecular Medicine
Undergraduate Institute: Johns Hopkins University
Research Advisor: Graeme Woodworth, M.D., Anthony Kim, Ph.D., and Jeff Winkles, Ph.D.
Description of Research
Triple-negative breast cancer (TNBC) represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. Fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor (TNFR) superfamily, is elevated in over a dozen solid cancer types, including TNBC. Moreover, as a result of its limited expression in normal tissues, Fn14 has the potential to be an ideal candidate for the development of targeted therapy and its down-regulation may contribute to positive disease outcomes. Most current chemotherapeutics have a non-specific mechanism of action and a poor biodistribution profile, which results in dose-limiting toxicities. Nanotherapeutics is a burgeoning field in cancer therapy that may address some of the issues associated with systemically administered drugs. However, many of the nanoparticle (NP) formulations approved for clinical use in solid tumor therapy provide only modest improvements in patient survival. This is in part due to NP tumor penetration barriers, including a dense and complex extracellular matrix (ECM) and an elevated interstitial fluid pressure, which hinder the penetration of drugs and NPs into and within tumors limiting therapeutic efficacy. My thesis project will test the hypothesis that paclitaxel (PTX)-loaded Fn14-targeted NPs with a dense, low-molecular weight PEG coating will inhibit Fn14-positive TNBC xenograft growth due to their ability to specifically target and penetrate tumor tissue. I will test this hypothesis in the following Specific Aims: 1) Determine the optimal size and PEG density for efficient tumor tissue penetration of model polystyrene NPs. 2) Study the non-specific binding, particle diffusivity, and tumor penetrating capability of drug-loaded, PLGA non-targeted and Fn14-targeted NPs. 3) Evaluate the therapeutic efficacy and toxicity of PTX-loaded non-targeted PLGA NPs, PTX-loaded Fn14-targeted PLGA NPs, and Abraxane following systemic administration into mice bearing either Fn14-positve MDA-MB-231 or TNBC patient-derived xenografts.