Abstract P6-15-09: Insulin-Like Growth Factor Receptor I (IGF1R) Inhibitors May Be Synergistic with Chemotherapy in Basal Breast Cancer
Authors: Offor O , Sullivan C , Rodov S , Lezon-Geyda K , Zerillo C , DiGiovanna M , Harris L. 
Published: April 2011

Background: Preclinical and clinical data show associations between basal breast cancer (BBC) and obesity, insulin resistance and metabolic syndrome suggesting a role for the insulin-like growth factor (IGF) pathway in this disease. We hypothesized that IGF1R targeted therapy will be active in BBC and would enhance the activity of chemotherapeutic agents. We evaluated AG1024, a kinase inhibitor of IGF1R, and Figitumumab, a human anti-IGF1R antibody, in BBC cell lines as monotherapy and in combination with conventional chemotherapeutic agents, doxorubicin or paclitaxel.

Materials and Methods: To evaluate the effect of AG1024, Figitumumab, doxorubicin and paclitaxel, growth assays were conducted using four BBC cell lines (MDA-MB-231, MDA-MB-468, SUM149 and BT20) and the ER positive control cell line, MCF7. Cells were harvested, resuspended in OptiMEM and plated in triplicate at optimal cell densities (50-70% confluent). AG1024 (0-µM), Figitumumab (0-0.585μM), doxorubicin (0-0µM) and paclitaxel (0-20nM) were added after 24-hour incubation. On Day 5, at 70-90% confluence, the cell proliferation Reagent WST-1 (Roche) was added, cells incubated and OD measured as directed by the manufacturer. The percent of surviving cells in each test well was calculated as follows: OD drug-treated well/untreated mean x 100. Each drug combination was assessed in triplicate. Using CalcuSyn (BioSoft), the Median Effects method described by T-C Chou and P. Talaly was used to determine whether or not drug combinations were synergistic or additive. A combination index (CI) &lt;0.90 = synergism, between 0.90 and 1.10 = additive and &gt;1.10 = antagonism. The CI values reported were observed in two or more experiments.

Results: AG1024 produced dose-dependent growth inhibition in all BBC cell lines.

Cytotoxicity of AG1024 (40uM) after a five day incubation.

The hormone-receptor positive MCF7 cell line was the least sensitive to AG1024. Figitumumab had no activity as monotherapy on BBC and control cell lines. Combination therapy with AG1024 and chemotherapy produced synergistic or additive effects in all BBC cell lines. For instance, combining 01µM doxorubicin with 1µM AG1024 produced a synergistic effect in all BBC cell lines except MDA-MB-468.

Combination Indices (CI) of combination therapy experiments.

Similarly, Figitumumab and chemotherapy produced additive or synergistic growth inhibition. Further data on IGF1R levels and phosphotyrosine activity will be presented

Conclusions: AG1024 causes a dose-dependent decrease in cell viability in BBC cell lines produced synergistic cytotoxicity with paclitaxel and doxorubicin. Figitumumab alone failed to have cytotoxic effects on BBC cell lines, however additive or synergistic effects were seen with paclitaxel or doxorubicin in combination with Figitumumab. The combination of IGF1R inhibitors with chemotherapy in BBC should be further explored.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-09.