Abstract 2795: Safety profile and therapeutic potential in breast cancer of STX140, an original tubulin binding agent

Abstract

Abstract STX-140 is an anti-tubulin binding agent which has demonstrated a good anti-tumor efficacy profile. Although the binding site on tubulin differs from other classical tubulin binders, one could anticipate the same type of safety issues with such an agent, namely neurotoxicity. In order to differentiate this compound, we evaluated its efficacy in a transgenic model of mammary cancer, its neurotoxicity potential, and its therapeutic index in a breast cancer model. STX140 efficacy was evaluated in C3(1) Tag transgenic mice which develop mammary carcinomas. In those transgenic animals, the disease progresses in a similar fashion to human breast cancer, with the development of tumors which show the same histological characteristics as the human pathology. In these mice, STX140 was able to significantly increase the survival of the animals and to suppress the emergence of metastases, whereas paclitaxel was completely inactive on both parameters. Neurotoxicity potential was assessed in a thermal hyperalgesia model in comparison with paclitaxel. Continuous oral treatment of mice with STX-140 did not induce an increase sensibility to heat as measured by the latency of paw withdrawal after a heat stimulus. However, paclitaxel increased this heat sensitivity starting after the second i.v. administration, underlying the neurotoxicity of this compound, which is observed in the clinic. Finally, in MDA-MB-231 breast cancer xenografts, two different schedules of oral administration were evaluated in order to determine the therapeutic index and PK parameters were measured in parallel to the anti-tumor efficacy. Continuous (QD) and intermittent (Monday, Wednesday, Friday; MWF) treatments were evaluated and a large panel of doses were tested. The therapeutic index was determined as the ratio of the exposure observed between the first toxic dose and first active dose. The TI for the QD schedule was 2.1 and was 1.7 for the MWF schedule, showing the potential good safety index of this compound. Taking into account the previous data reported elsewhere and new data presented here, which underline the great efficacy and safety profile of STX140, this compound is considered for further preclinical and clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2795. doi:1538-7445.AM2012-2795