Abstract LB-283: Novel small molecule has potent antitumor activity in drug-resistant human carcinoma xenograft models

Abstract

We have previously shown that Kevetrin, a novel molecule currently under development, was effective in reducing tumor growth in human multi-drug resistant lung cancer xenograft models while being well tolerated. In this study, we expanded our tests to include other tumor types: colon and breast. Three of the models have been shown to be multi-drug resistant: HCT-15 colon carcinoma have an overexpression of p-glycoprotein that acts as a membrane efflux pump (Iwahashi 1991, Mickley 1989), MDA-MB-435s carcinoma cells have highly active c-Abl and Arg kinases and overexpress Heat Shock Protein 27 which inhibits apoptosis thereby contributing to drug resistance (2006 Srinivasan, 2008 Shi), and A549 lung carcinoma have the K-ras mutation and overexpress STAT3 and Nrf2; mutations associated with resistance to standard chemotherapy (Akudela 2004, Mahaffey 2009, Homma 2009, Kim 2009). To demonstrate a dose response effect, in the multi-drug resistant A549 lung tumor model, nude mice bearing established tumors were treated with either 50, 100, or 200 mg/kg Kevetrin intraperitoneally (IP) every other day for 3 doses or 200 mg/kg every other day for 3 doses followed by a second cycle 10 days later. Kevetrin delayed median tumor growth in a dose dependent manner where 50, 100, and 200 mg/kg produced tumor growth delays (TGDs) of 0%, 6%, and 21%, respectively, relative to controls. When given in 2 cycles at 200 mg/kg, a significantly greater TGD of 35% was achieved. In the HCT-15 multi-drug resistant colon tumor model, nude mice bearing established tumors were treated with either 200 mg/kg Kevetrin IP every other day for 3 doses or 22 mg/kg paclitaxel intravenously (IV) daily for 4 doses. Paclitaxel had no anti-tumor activity, whereas Kevetrin produced a significant TGD of 16 days (43%) relative to controls. In a non drug-resistant colon tumor model, HT-29, Kevetrin produced a similar TGD of 18 days (49%) while 20 mg/kg 5-fluorouracil (5-FU) IP given daily for 5 doses produced a TGD of 9 days (24%). In the MDA-MB-435s drug resistant tumor model, nude mice bearing established tumors were treated as above. Paclitaxel had no significant anti-tumor activity (1% TGD), whereas Kevetrin produced a significant TGD of 20 days (65%). In a non drug-resistant breast tumor model, MDA-MB-231, Kevetrin produced a TGD of 26 days (90%), and paclitaxel produced a significant TGD of 18 days (62%). These results demonstrate that Kevetrin exerted potent anti-tumor activity against three different tumor types, e.g., lung, breast, colon, including those that have multi-drug resistant phenotypes at doses and schedules that were well-tolerated as suggested by <5% weight loss during treatments. Therefore, these studies suggest that Kevetrin has promising potential for the treatment of tumors that have become resistant to standard chemotherapy. Based on our studies we plan to initiate a Phase I clinical trial in solid tumors in 2010. 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 LB-283.