Download 2016 department of medicine research day

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 ].