Abstract 831: BAL101553 (prodrug of BAL27862): A unique microtubule destabilizer active against drug refractory breast cancers alone and in combination with trastuzumab
Authors: Felix Bachmann, Karin Burger, George E. Duran, Branimir I. Sikic, Heidi A. Lane
Journal: Cancer Research (2014)

Abstract Background: BAL101553 is a highly soluble prodrug of BAL27862, a novel, small molecule, microtubule (MT)-depolymerizing agent with a broad in vitro anti-proliferative activity against human tumor lines refractory to standard microtubule-targeting agents (MTAs). The BAL27862 MT phenotype is distinct from standard MTAs (eg taxanes; vinca-alkaloids) and the prodrug has antitumor activity in diverse mouse tumor models when given orally or iv. In this study, activity was assessed in experimental breast cancer models alone and in combination with the ErbB2-targeted therapeutic antibody trastuzumab. Methods: Anti-proliferative activity was analyzed using monolayer or soft agar assays, MT phenotypes by immunofluorescence for α-tubulin and efficacy in mouse xenograft models of human breast tumors. Results: Potent anti-proliferative activity was observed in 8 of 9 breast cancer lines (IC50 range of sensitive lines: 8 - 25 nM) associated with the characteristic BAL27862 MT phenotype (tiny MT asters in G2/M arrested cells). Interestingly, 2 breast cancer lines were sensitive to BAL27862 in a clonogenic assay (IC50/IC70 - MAXF 401: 13/18 nM; MX1: 22/46 nM) despite one being relatively resistant to paclitaxel (MX1: 127/&amp;gt;3500 nM). Moreover, BAL27862 retained activity in 2 Pgp drug efflux pump-expressing breast cancer lines, 50 - 100-fold resistant to paclitaxel and vinblastine (MT-3/ADR, MCF7/TxT50), as well as in MCF7/TxTP50 cells ∼8-fold resistant to paclitaxel through non-Pgp-related mechanisms. When administered iv to mice at well tolerated doses, BAL101553 elicited statistically significant antitumor activity (p&amp;lt;0.05 vs. controls) in chemo-sensitive (MT-3) and chemo-refractory (MT-3/ADR) mammary xenografts, resulting in a final %T/C (ratio of mean tumor volume of treated and control group x 100) superior to comparator cytotoxics (MT-3: 35 % BAL101553, 54% paclitaxel, 104% vincristine; MT-3/ADR: 38% BAL101553, 118% paclitaxel, 103% vincristine). Antitumor activity was also observed in trastuzumab-sensitive (BT474) and-refractory (MaCa3366) ErbB2-overexpressing breast cancer xenografts, and in bulky BT474 tumors insensitive to trastuzumab treatment. Moreover, combination of BAL101553 and trastuzumab was well tolerated, with a striking enhancement of antitumor activity in the trastuzumab refractory MaCa336 model (% T/C - 56% BAL101553, 97% trastuzumab, 32% combination; p&amp;lt;0.05 vs. control or trastuzumab alone) which was associated with a significant delay in tumor growth over an extended time period (p=0.002 vs. controls). Conclusions: BAL101553 is currently undergoing Phase 1 clinical evaluation in advanced cancer patients with solid tumors. Potent antitumor activity alone and in combination with trastuzumab in preclinical chemo-refractory models of breast cancer supports clinical evaluation in breast cancer patients. Citation Format: Felix Bachmann, Karin Burger, George E. Duran, Branimir I. Sikic, Heidi A. Lane. BAL101553 (prodrug of BAL27862): A unique microtubule destabilizer active against drug refractory breast cancers alone and in combination with trastuzumab. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 831. doi:10.1158/1538-7445.AM2014-831