Abstract LB-151: The novel tubulin-binding, tumor checkpoint controller BAL101553 has differential effects on tumor vascularization with IV and oral dosing and provides superior anti-tumor activity in combination with bevacizumab

Abstract

Abstract Background: BAL101553 is a highly soluble prodrug of BAL27862, a novel, small molecule, microtubule-depolymerizer inducing tumor cell death through the spindle assembly checkpoint. BAL101553 has anti-cancer activity in diverse tumor models refractory to standard therapies, and is currently undergoing Phase 1/2a evaluation in advanced cancer patients with IV (weekly) and oral (daily) dosing schedules. Here, the vascular disruption activity of BAL101553 was evaluated in the context of administration route and implications for combinations with VEGF-targeted therapies. Methods: MTD IV (day[d] 1) and oral (d1 & d1 - 4) dosing regimens were tested in H460 NSCLC xenografts. Tumors were analyzed by IHC for proliferation (Ki67) and vascularization (CD31, lectin perfusion). Drug combinations were performed in Pgp-overexpressing, colon carcinoma SW480 xenografts using BAL101553 IV 1xweek (21.3 mg/kg) or oral daily (15 mg/kg) and bevacizumab IP d1 & 4 (5 mg/kg). Results: H460 tumor-bearing mice received once weekly (IV 25 mg/kg; oral 60 mg/kg; high Cmax regimens) or daily (oral 25 mg/kg; low Cmax, high AUC) BAL101553 regimens which elicited equipotent anti-tumor effects (ΔT/Cs = 26-34%). Although all treatments elicited a similar anti-proliferative response (% reduction of mean Ki67 signal+/-SD=10+/-1.2; p<0.05 vs. controls), tumor vessel density was most profoundly reduced by high Cmax regimens. Interestingly, daily-oral treatment (low Cmax, high AUC) had reduced tumor anti-vascular activity, while presenting equivalent anti-proliferative and anti-tumor efficacy. In vitro assays against tumor cell lines showed that sub-cytotoxic BAL27862 concentrations reduced HIF-1α protein levels in normoxic and hypoxic conditions, diminishing VEGF-expression and secretion, indicating direct interference of the drug on hypoxic adaptation and endothelial tube formation. Based on these data, combination of the anti-VEGF antibody bevacizumab with BAL101553 was assessed in the paclitaxel refractory SW480 tumor model, using MTD BAL101553 dosing (IV weekly & oral daily). All monotherapies induced an anti-tumor response (ΔT/Cs bevacizumab: 35%; IV BAL101553 22%; oral BAL101553: 53%). However, bevacizumab combined with IV or oral BAL101553 was superior to single agents (ΔT/C: 6% and 17%, resp., p<0.05 vs. control) with IV combination associated with the least functional tumor vasculature. Conclusions: BAL101553 targets tumor cell proliferation, tumor hypoxic adaptation and vascularization. The latter is Cmax-driven and can be attenuated by daily oral dosing, providing an alternative pharmacodynamic endpoint with implications for clinical treatment strategies. IV and orally administered BAL101553 both elicit superior anti-tumor responses in combination with anti-VEGF therapy. Citation Format: Ashish Sharma, Felix Bachmann, Angela Broggini-Tenzer, Matthias Guckenberger, Heidi Lane, Martin N. Pruschy. The novel tubulin-binding, tumor checkpoint controller BAL101553 has differential effects on tumor vascularization with IV and oral dosing and provides superior anti-tumor activity in combination with bevacizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-151. doi:10.1158/1538-7445.AM2017-LB-151