Abstract 2538: A novel therapeutic strategy for malignancy: Specific disruption of FAK and IGF-1R interaction with a small molecule compound

Abstract

Abstract Introduction: Pancreatic cancer and other aggressive malignancies are associated with poor patient survival rates. FAK and IGF-1R are two important tyrosine kinases important for cell survival signaling and found to be upregulated in several malignancies. As a novel strategy, we targeted FAK and IGF-1R protein interactions with a small molecule compound that altered crucial signaling pathways, and hypothesized that this approach would significantly inhibit cell proliferation and lead to apoptosis both alone and in combination with chemotherapy. Methods: The compound C31 (INT2-31) was identified from a high throughput screen to bind to FAK and disrupt protein-protein interactions. The effects of this compound when administered alone or together with 5-FU, gemcitabine or dacarbazine chemotherapy on cell signaling, viability and apoptosis in human pancreatic (Miapaca-2, Panc-1) esophageal (KYSE 70, 140) and melanoma (A375, C8161, SK-Mel28) cancer cells or on in vivo growth of direct human cancer xenografts was evaluated. Statistical analysis via t-test with significance defined as p<0.05. Results: INT2-31 caused a disruption of protein interactions between FAK and IGF-1R in whole cancer cell lysates starting at a concentration of 2.5 μM. It also caused a dose dependent inhibition of cell viability and induction of apoptosis starting at doses of 0.5 µM and 5µM, respectively. These effects were associated with a decrease in phosphorylation of Akt and ERK1/ERK2. INT2-31 treatment, when administered via subcutaneous or intraperitoneal injection, at 15 to 50mg/kg daily, resulted in a significant decrease of in vivo tumor growth in multiple cells lines in the subcutaneous or orthotopic pancreatic model as well as inhibition of growth of direct cancer xenografts. For instance, the size of a direct esophageal cancer subcutaneous xenograft was significantly decreased in INT2-31 treated animals vs control (236 +131 vs 931 +375 cm3, respectively, p<0.005). Tumor Ki67 staining from INT2-31 treated animals demonstrated a significant decrease in positive cells (52% vs 32%, control vs INT2-31, p<0.05). Furthermore, treatment with 5-FU chemotherapy resulted in a synergistic decrease in cell growth and increase in apoptosis when combined with INT2-31 compared to 5-FU or INT2-31 alone. Conclusions: A novel small molecule compound that disrupts the protein interactions of FAK and IGF-1R results in significantly decreased cancer cell proliferation and sensitizes cells to chemotherapy. These effects appear to be mediated through downregulation of p-AKT and p-ERK. This compound deserves further study as a novel treatment strategy in patients with solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2538.