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2016 DEPARTMENT OF MEDICINE RESEARCH DAY Title of Poster: Preclinical Development of Metformin Derivatives that inhibit the progression of human triple-negative breast cancer and pancreatic cancer Presenter: Cristian Yanes Division: Hematology-Oncology ☐ Faculty ☐ Fellow ☐ Resident ☐ Post-doc Research Fellow ☐ Graduate Student ☐ Medical Student ☒Other (Undergrad) Principal Investigator/Mentor: Richard J. Pietras Co-Investigators: Michael E. Jung, Diana C. Márquez-Garbán, Gang Deng, Emelyne Diers, Nalo Hamilton, David Elashoff Thematic Poster Category: Development, Morphogenesis, Cell Growth and Differentiation, Apoptosis, Stem Cell Biology, Carcinogenesis and Cancer Biology Abstract Use of metformin, the most commonly-prescribed drug for treatment of type 2 diabetes mellitus, has been repeatedly associated with reduced risk for occurrence of various types of cancers, including breast and pancreatic cancers. Triple-negative breast cancers (TNBC) lack clinical expression of estrogen receptor-alpha, progesterone receptor and HER2 receptor overexpression and cannot be treated with current endocrine or HER2-targeted therapies. TNBC occurs in only 10-15% of all patients with breast cancer, yet this disease accounts for almost half of all breast cancer deaths. TNBCs are heterogeneous, with most, but not all, categorized as basal-like on gene expression analyses, and TNBC occurs often in younger and African American women and among those with BRCA mutations. Although initially responsive to some cytotoxic chemotherapies, TNBCs tend to relapse early and metastasize, leading to poor patient survival. It is urgent to develop new therapeutics to target this deadly disease. Diabetic patients treated with metformin have a reduced incidence of and better survival from breast cancer. Moreover, TNBC cells are reported to be highly sensitive to metformin due to their unique metabolic requirements. However, despite these promising data on antitumor effects of metformin, caveats remain. Epidemiologic studies on metformin effects were largely based on retrospective data and were not randomized; and antitumor effects of metformin observed in preclinical experiments appear to be markedly enhanced at higher doses of the drug or by IV administration at dose levels that would not be achievable in the clinic without undesired toxicities. Thus, we hypothesize that it may be feasible to design and synthesize structural analogues of metformin with even more potent anticancer activity and target specificity than the parent drug metformin. We now report on development of novel metformin analogues with superior antitumor effects based on preclinical TNBC and pancreatic tumor models. We tested metformin and new structural analogues of metformin in TNBC and in estrogen receptor-positive MCF-7 cells. Using cell proliferation assays, cells were treated for 72 hours in the presence of metformin or analogues. Inhibition of cell proliferation was dose-dependent and significant at low concentrations (0.01-1mM) of metformin analogues (P <0.01) in TNBC cell lines (MDA-MB-231, HCC1937, HCC1806 and HCC38) but not in nonmalignant control cells. The antitumor effects of metformin in breast and other tumors have been attributed largely to activation of the LKB1-AMPK pathway, leading to inhibition of mTORC1 and downstream signaling. Similarly, we find that stimulation of TNBC cells with metformin analogues for up to 24 hrs stimulates phosphorylation of AMP kinase as determined by PAGE/Western immunoblots. Furthermore, metformin analogues significantly reduce the downstream phosphorylation of mTORC1 signaling pathway components (p70 S6K, S6 ribosomal protein and 4E-BP1). TNBC xenograft studies on the activity of metformin analogues confirm that selected analogues when administered by oral gavage daily can effectively suppress tumor progression as compared to control treatments (P<0.001). Likewise, growth of pancreatic cancer cell tumor xenografts was inhibited when metformin analogues were administered by oral gavage (P<0.001). These studies suggest that selected analogues of metformin have potent anticancer activity in preclinical work with TNBC and pancreatic cancer cells. This comprehensive structure-activity research on the antitumor activity of metformin has not been done before. Since there are currently no targeted treatments for TNBC or pancreatic cancer in the clinic, identification of a new targeted therapeutic could be very significant for patients afflicted with these deadly diseases. [Funded by JCCF, Stiles Program in Oncology, Hickey Foundation, Tower Cancer Research Foundation-Jessica M. Berman Breast Cancer Fund, NIH U54 CA143930, and NIH 5R21 CA176337 ].