The overall goal of this project is to investigate whether dehydro-alpha-lapachone (DAL) represses cancer cell motility, inhibits of primary tumor growth and reduces of metastatic burden in preclinical models of triple negative breast cancer. Our preliminary data indicate that DAL is a chemical agent with prominent anti-tumor effect and low toxicity toward normal tissues. Through the dissection of underlying molecular mechanisms, we have shown that DAL 1) represses the Rho-GTPase Rac1, which increases cancer cell motility through remodeling of the actin cytoskeleton, and 2) allosterically inhibits indoleamine-2,3-dioxygenase (IDO), which may confer immunosuppressive characteristics in tumors. We will study DAL's effects on cancer cell motility and invasion (Aim 1), DAL's influence on anti-tumor immunity (Aim 2) and DAL anti-metastatic efficacy (Aim 3). The experiments proposed will enable that DAL represses metastasis and invasion of the most aggressive subtype of breast cancer. To test this hypothesis we will utilize mouse models of spontaneous metastasis and in vitro models evaluating the effects of DAL on motility of cancer cells. The proposed research will clarify the role of cancer-host interaction in metastasis formation and contribute to the development of breast cancer metastasis prevention strategies based on potential novel therapeutic targets Rac1 and IDO.
Triple-negative tumors (estrogen receptor-negative, progesterone receptor-negative, and C-erbB-2-negative) represent the most aggressive breast cancer subtype and have the worst prognosis despite advancements in modern therapeutics. To improve the diversity of options for anti-tumor and anti-metastatic therapy for this subtype of cancer, we applied a high-throughput screen for small molecules and identified a nontoxic natural plant product (DAL). Here will study whether DAL represses cancer cell motility, subsequent inhibition of primary tumor growth and reduction of metastatic burden in preclinical models of triple negative breast cancer.
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|Kozin, Sergey V; Maimon, Nir; Wang, Rong et al. (2017) Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers. Oncotarget 8:108292-108302|
|Garkavtsev, Igor; Chauhan, Vikash P; Wong, Hon Kit et al. (2011) Dehydro-alpha-lapachone, a plant product with antivascular activity. Proc Natl Acad Sci U S A 108:11596-601|