This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Signal transduction inhibitors (STIs) are a new class of anticancer agents that are highly selective in their action, acting on molecular targets that are integral in the progression of cancer. Many of these new STIs are large (500 Da) and lipophilic (LogPo/w 5) presenting significant challenges in formulation, including poor water solubility, limited stability, wide volumes of distribution, and non-specific toxicities. Our goal is to develop nanocarrier formulations of STIs for single agent and combination therapy in cancers, which are high responsive to treatment with the proposed STIs. We will evaluate the STIs geldanamycin (GA) and rapamycin (RAPA) as single agents and in combination against rodent breast cancer xenografts using a safe, biocompatible amphiphilic block copolymer (ABC) micelle formulation. We hypothesize ABC micelles will enhance the efficacy of these potent agents by avoiding clearance by the mononuclear phagocyte system, resulting in preferential accumulation at solid tumors through leaky blood vessels. Combination of RAPA and GA is reported to be synergistic in vitro against multiple myeloma.
Our aims are to 1) investigate the combination of these STIs in vitro, 2) formulate them using a micelle nanocarrier, and 3) investigate these formulations in vivo in murine tumor models. In summary, this study seeks to establish the efficacy of RAPA and GA in breast cancer in vitro and in vivo using nontoxic ABC micelle nanocarrier formulations of single agents and combinations, providing new formulations of novel STIs for treatment of breast cancer in humans.
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