EMD-1214063

Cell lines

Triple-negative breast cancer cell lines (MDA-MB-468, HCC-1395, and MDA-MB-231) and hormone receptor positive cell line (T47D)

Preparation Method

Cells were seeded in 96-well microplates in medium supplemented with 5% FBS and penicillin/streptavidin. The optimal cell number for each cell line was determined to ensure that each was in growth phase at the end of the assay (~70% confluency). Cells were allowed to attach for 24 hours. The media was changed to low FBS (2%) and drugs with different combinations were added (cetuximab 200ug/mL, gefitinib 0.25-8 umol/L and EMD-1214063 2-10 μM). Cells were incubated at 37°C for 72 hours.

Reaction Conditions

2-10 µM for 72 hours

Applications

These cell lines were essentially resistant to both gefitinib and EMD-1214063 as single agents. The inhibitory effect of combined treatment with gefitinib and EMD-1214063 was significantly enhanced compared with single agent therapy in MDA-MB-468 cells but not in the other cell lines (MDA-MB-231, HCC1395, and T47D)

Animal models

BALB/c nude male mice

Preparation Method

The patient-derived hepatocellular carcinoma (HCC) cells were subcutaneously inoculated in male BALB/c nude mice. When the tumors reached approximately 1 cm in diameter, subcutaneous tumors were collected and cut into pieces of about 2–3 mm3 and inoculated into the left lobe of the liver of male BALB/c nude mice.Mice were treated orally five days on/two days off with either vehicle combination (n = 10; 20% Solutol/80% 100 mM Na-acetate buffer, pH 5.5 ), EMD-1214063 (n = 10; 10, 30, or 100 mg/kg), sorafenib (n = 10; 50 mg/kg), or rapamycin (n = 10; 3 mg/kg) as single-agent treatment. In addition, EMD-1214063 (10 mg/kg) was given as a combination treatment with sorafenib (n = 10, 50 mg/kg) or rapamycin (n = 10; 3 mg/kg). Treatment was started seven days after orthotopic implantation of tumor fragments and terminated after five weeks.

Dosage form

10, 30, or 100 mg/kg/d, five days on/two days off , oral

Applications

The intrahepatic tumor size and weight were significantly lower in EMD-1214063 treated mice compared to the control group. EMD-1214063 treatment reduced the number of metastatic foci in the lungs of mice bearing orthotopic MHCC97H tumors, compared to the control group.

References:

[1] : Sohn J, Liu S, Parinyanitikul N, et al. cMET activation and EGFR-directed therapy resistance in triple-negative breast cancer[J]. Journal of Cancer, 2014, 5(9): 745.

[2] :Bladt F, Friese-Hamim M, Ihling C, et al. The c-Met inhibitor MSC2156119J effectively inhibits tumor growth in liver cancer models[J]. Cancers, 2014, 6(3): 1736-1752.