Abstract P6-15-08: KGFR Tyrosine Kinase Inhibitors for the Treatment of Breast Cancer

Abstract

Abstract Background: Keratinocyte growth factor (KGF) produces a rapid increase in the proliferation and motility of estrogen receptor (ER)-positive breast cancer cells (Zang, XP and Pento, JT, Clin. & Exptl. Metastasis 18: 573-80, 2001). It has been demonstrated that the KGF receptor (KGFR) is up-regulated in breast cancer; thus, KGF/KGFR signaling appears to be an early event in breast cancer progression (Zang, XP, Lerner, ML, Bahr, SJ, Brackett, DJ and Pento, JT, Cancer Genomics & Proteomics, 3: 369-72, 2006). Molecular modeling was used to create group of KGFR selective tyrosine kinase inhibitors (TKI) (Pento, JT and Li, PK, Drugs of the Future, 32: 965-72, 2007). The present study examined the effect of a group of these compounds on KGF-mediated proliferation and Erk signaling in MCF-7 breast cancer cells. In addition, the oncolytic potential of compound L-27, a potent KGFR TKI, was examined in an orthotopic xenograft model of human breast cancer. Methods: A group of high affinity KGFR TKI were tested for their ability to inhibit KGF-mediated proliferation and Erk phosphorylation in MCF-7 cells using MTS and ELISA assays. In addition, immuno-cytochemistry was used to examine the influence of the 5 most potent inhibitor compounds on the density of cell membrane KGFR. The effects of a KGFR TKI on breast cancer growth and progression in vivo was examined using an orthotopic xenograft model, with clones of MCF-7 cells which were transfected with a KGF-producing plasmid to enhance cell growth and metastasis and a GFP reporter to quantify tumor growth and metastasis. PET imaging was also used to identify metastatic development. Results: From the initial group of 53 compounds, 5 compounds were observed to produce greater than 50% inhibition of KGF-mediated cancer cell proliferation, reduce Erk phosphorylation and the density of the KGFR on the membrane surface of the cancer cells. Compound L-27, one of the most potent KGFR inhibitors, reduced the growth of MCF-7 tumors and metastatic development in the xenograft model in a dose-related fashion at doses of 4, 10 and 25 mg/kg. Animal weights in the treatment groups remained the same as the control group; indicating a lack of toxicity at the doses employed. Discussion: The novel compounds tested in this project reduce or abolish KGF-mediated proliferation, Erk signaling and KGFR membrane density in vitro. In addition, compound L-27, a potent KGFR inhibitor in vitro, was found to reduce the progression of MCF-7 tumor xenografts in vivo. In conclusion, the KGFR TKI represent a novel class of anticancer agents for the prevention of metastatic progression and may provide a new therapeutic approach for the treatment of breast and other cancers. Acknowledgement: This work was supported by the grants from DoD (DAMD17-01-1-0591) and the NCI (CA-89740) and (CA-125493). Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-08.