Abstract C49: AKT inhibitor has potent antitumor activity in human lung cancer xenograft models

Abstract

Lung cancer accounts for more than 215,000 new cases annually in the United States, and is the single largest cause of cancer death accounting for more than 130,000 deaths each year. Non-small cell lung cancer (NSCLC) accounts for 80% of all bronchogenic neoplasms with 90% of diagnosed patients dying within five years; therefore, new therapies are strongly desired. Effective therapies will come from a more detailed understanding of the molecular mechanisms underlying both the disease and the clinical response. We are developing a novel molecule, termed Kevetrin™, which was effective in reducing tumor growth in human lung cancer xenograft models while being well-tolerated. Kevetrin appeared to exert its anti-tumor activity by lowering levels of activated AKT also known as protein kinase B, of the AKT signal transduction pathway resulting in reduced tumor cell survival. Activated AKT was measured by a sandwich ELISA specific for phosphorylated AKT protein. Kevetrin was also evaluated for anti-tumor activity in vivo in the NCI-H1975 and A549 lung xenograft tumor models. Tumor-bearing nude mice were treated intravenously (IV) with either 200 mg/kg Kevetrin three times every other day or 22 mg/kg paclitaxel four times every other day. After Kevetrin was incubated with cells in vitro, phosphorylated AKT levels were reduced leading us to test for anti-tumor activity in vivo. Results with NCI-H1975 tumors showed that Kevetrin significantly delayed median tumor growth by 34 days (142%) in the first experiment and 28 days (156%) in a repeat experiment compared to controls, whereas the tumor growth delay (TGD) of paclitaxel was just 4 days (17%) and 14 days (78%), respectively. No weight loss occurred during treatment with Kevetrin. Results with A549 tumors showed that Kevetrin significantly delayed median tumor growth by 11 days (33%) in the first experiment and 30 days (111%) in a repeat experiment compared to controls, whereas the TGD of paclitaxel was just 0 days (0%) and 3 days (11%), respectively. In this study, Kevetrin resulted in <5% weight loss during treatment. These results showed that Kevetrin exerted potent anti-tumor activity against two human lung xenograft tumor models, NCI-H1975 and A549, at a dose and schedule that was well-tolerated as indicated by a small transient weight loss during treatment. NCI-H1975 have the T790M and L858R mutations in epidermal growth factor receptor (EGFR) and A549 have the K-ras mutation and overexpress STAT3 and Nrf2; these mutations are associated with resistance to standard chemotherapy. The reduction of activated AKT may be a mechanism by which Kevetrin overcame resistance and showed efficacy in these tumor models. These studies demonstrate that Kevetrin has promising potential for the treatment of lung carcinoma, particularly in cases where tumors have become resistant to standard chemotherapy. Citation Information: Cancer Res 2009;69(23 Suppl):C49.