BAL27862: A Unique Microtubule Destabilizer Active Against Chemorefractory Breast Cancers. (2009)

Abstract Background: BAL27862, a novel, synthetic, small molecule, is a potent inhibitor of tubulin polymerization that induces cancer cell death. BAL27862 elicits a unique microtubule (MT) phenotype, distinct from paclitaxel, vinblastine and colchicine, has broad in vitro anti-proliferative activity against a diverse range of human tumor lines (low nM IC50s) and induces significant antitumor responses in a range of animal models of human cancer when administered orally (p.o.) or intravenously (i.v.). In this study, BAL27862 activity in a panel of experimental breast cancer models was assessed.Materials and Methods: Anti-proliferative activity was analyzed using a monolayer (crystal violet) or soft agar (clonogenic) assay. Effects on MT phenotypes were assessed by immunofluorescence for α-tubulin. Efficacy was assessed in mouse xenograft models bearing chemosensitive and multidrug resistant human breast tumors.Results: The unique BAL27862-associated MT phenotype in interphase cells consisted of a partially collapsed MT network without peripheral MTs. In dividing cells, tiny MT asters were found scattered within the nuclear region. Potent anti-proliferative activity was demonstrated against 8 breast cancer cell lines (crystal violet assay IC50 range: 6.5 – 22 nM for the SKBR3, MCF7, BT474, T47D, BT549, MDA-MB231, MDA-MB453 and MDA-MB468 lines), although one line (HCC1937) appeared relatively insensitive (IC50: &gt;1000 nM). Interestingly, two breast cancer lines were sensitive to BAL27862 treatment in a clonogenic assay (IC50/IC70: MAXF 401 = 13/18 nM; MAXF MX1 = 22/46 nM), despite one being relatively resistant to paclitaxel treatment (MAXF 401 = 11/48 nM; MAXF MX1 = 127/&gt;3500 nM). Moreover, using monolayer assays, BAL27862 activity was retained against five tumor lines overexpressing the Pgp efflux pump (including MT-3/ADR mammary adenocarcinoma cells), which were up to several thousand-fold resistant to paclitaxel and vinblastine. BAL27862 showed little activity against human stem cells or peripheral blood mononucleocytes.When administered p.o or i.v. to mice at well tolerated doses, BAL27862 treatment elicited statistically significant antitumor activity (p≤0.05) in three chemosensitive human breast tumor xenograft models (including MAXF 401, MaCa 4049 and MT-3); resulting in a final %T/C (ratio of mean tumor volume of treated and control group x 100) equivalent to that observed with comparator cytotoxics using MTD schedules (e.g. final %T/C in MT-3 model: 36% BAL27862, 35% paclitaxel, 50% doxorubicin). Strikingly, significant antitumor activity was maintained in the Pgp-overexpressing MT-3/ADR xenograft model, where paclitaxel and doxorubicin were ineffective (final %T/C: 37% BAL27862, 112% paclitaxel, 108% doxorubicin).Conclusions: BAL27862 is a new tubulin-interacting agent with an apparently novel mechanism of action. A potent antitumor activity in experimental models of breast cancer, including chemorefractory models, strongly support further development of BAL27862 as a novel breast cancer treatment modality with a possibility for both i.v. and p.o. administration. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2093.