The management of advanced stage breast cancer (BC), especially, triple negative BC (TNBC) is exceptionally difficult due to the poor response to available therapeutic modalities. Poor survival is primarily because of suboptimal drug delivery and chemo-resistance due to excessive fibrosis and extracellular matrix deposition (desmoplasia) in solid tumors. NF-kappaB, Wnt and Sonic Hedgehog (SHH) are key oncogenic signaling pathways that are involved in BC progression (including desmoplasia) and the development of resistance to chemotherapeutic drug modalities. Curcumin is a nutritional, anticancer and chemopreventive molecule. Recent studies demonstrate that curcumin has potent inhibitory effects on aforementioned oncogenic pathways and induces chemo/radio-sensitization in BC cells including TNBCs. However, curcumin has poor pharmacokinetics and lack tumor targeting. Therefore modifications to curcumin are needed for successful clinical use. Our preliminary data suggest that curcumin inhibits Wnt, NF-kappaB and SHH signaling and curcumin pre-treatment induces chemo-sensitization and enhances the efficacy of cisplatin treatment in cancer cells, including TNBC cells. Although promising in in vitro studies, free curcumin has poor pharmacokinetics and modifications to curcumin are needed for successful clinical use. Recently, we have engineered a novel curcumin loaded multi-layered magnetic nanoparticle (MNP-CUR) formulation (Patent # PCT/US2011/063723) for cancer therapeutic applications. Our published and preliminary data demonstrate antibody conjugation capability of CUR nanoformulations(s) effectively target tumors and inhibit tumor growth upon intra-tumoral injection. Hence, we hypothesize that our novel antibody-guided MNP-CUR will enhance the bioavailability of curcumin in tumors to attenuate tumor growth and sensitize BC cells to therapeutic drug (cisplatin) via suppression of oncogene signaling pathways and decreased desmoplastic reaction. Recent studies suggest a major role for cross-talk between tumor and stromal cells in the pathobiology of BC. A recent study demonstrates that MUC1 expression is positive in 94% of basal-like triple-negative breast cancers. Additionally, MUC1 peptide vaccine use for TNBC is in clinical trial. Thus, MUC1 is a well-studied and validated target for BC and TNBC. Therefore, we will use MNP-CUR conjugated anti-MUC1 MAbs for effective treatment of BC/TNBC. This targeted approach will improve the efficacy of BC therapeutics due to the synergistic action provided by curcumin and cisplatin while minimizing the side effects of these modalities by lowering their effective therapeutic dose. More importantly, this project will support highly competitive training for Ph.D. students and establish a rich research environment with the initiative to develop cancer nano-therapeutics. Incorporation of such advanced concepts and experiments into course curriculum is highly warranted in pharmaceutical science. These efforts will eventually lead to the development of effective and safe methods to treat breast cancer.
This Academic Research Enhancement Award proposal aims to develop a novel and innovative targeted nano- chemosensitization approach that will improve chemotherapy (cisplatin) outcome for advanced, chemo-resistant, and triple negative BC cancers (because most cancer deaths are associated with these BCs). The main implications of this study are 1) Development of a novel approach for simultaneous targeting oncogenic pathways (NF-keppaB, Wnt and SHH signaling) 2) Evaluation of lipid profile and drug reversion mechanisms 3) Development of an innovative approach for tumor specific chemo-sensitization 4) Improve therapeutic efficacy of cisplatin therapies and 5) Minimize normal organ toxicity of cisplatin via lowering effective drug dosage, which might have strong clinical implications in developing unique strategies for breast cancer treatment due to cisplatin chemosensitization. Additionally, this proposal strongly supports a highly competitive training for MS/PhD students and to establish a rich research environment on the forefront of developing cancer nano-technologies.
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