Abstract PD03-04: Discovery of metformin derivatives with potent antitumor activity in triple-negative breast cancer

Abstract

Abstract Due to the success of endocrine therapy, the mortality of patients with estrogen receptor-positive tumors has declined significantly in recent years. In contrast, triple-negative breast cancers (TNBC) lack clinical expression of estrogen and progesterone receptors and HER-2 receptor overexpression and cannot be treated with current endocrine or HER2-targeted therapies. TNBC occurs in only 10–15% of patients, yet this disease accounts for a large proportion of all breast cancer deaths. TNBCs are heterogeneous (with most, but not all, categorized as basal-like on gene expression analyses) and occur often in younger and African American women. Although initially responsive to some chemotherapies, TNBCs tend to relapse early and metastasize, leading to poor patient survival. It is urgent to develop new therapeutics. Emerging evidence from epidemiologic and preclinical work suggests that metformin, the most widely used drug to treat type 2 diabetes mellitus, exerts anticancer activity in breast cancer. Diabetic patients treated with metformin have a reduced incidence of and better survival from breast cancer. Moreover, TNBC cells are reportedly uniquely sensitive to metformin, and the antitumor effects of metformin appear to be enhanced at high doses of the drug or by IV administration. Thus, we reason that structural analogs of metformin can be designed and synthesized with even more potent anticancer activity and target specificity than metformin. We now report on development of novel metformin analogues with superior anti-TNBC effects based on preclinical 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-dependant and significant at low concentrations (0.01–1mM) of metformin analogues (P < 0.01) in TNBC cell lines (MDAMB231, HCC1937, HCC1806, HCC38 and CRL2335) but not in nonmalignant control cells. Metformin analogues also induced apoptosis in TNBC cells as determined by established methods. The antitumor effects of metformin in breast and other tumors have been attributed largely to activation of the LKB1-AMPK pathway. Similarly, we find that stimulation of TNBC cells with metformin analogues for 24 hours stimulates phosphorylation of AMP kinase as determined by PAGE/Western immunoblots. Furthermore, metformin analogues significantly reduced the downstream phosphorylation of mTORC1 signaling pathway components (p70 S6K, S6 ribosomal protein and 4E-BP1). Tumor xenograft studies on the activity of metformin analogues are in progress. These studies suggest that analogues of metformin have potent anticancer activity in preclinical work with TNBC cells. This structure-activity research on metformin has not previously been done. Since there are currently no specific treatments for TNBC in the clinic, identification of a new targeted therapeutic could be very significant for patients afflicted with this deadly disease. [Funded by JCCF, Stiles Program in Oncology]. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-04.