Abstract 1881: The microtubule-disrupting drug BNC105 is a potent inducer of apoptosis in AML patient samples
Authors: Inglis Daniel J. , Casolari Debora A. , Nguyen Tran , Beaumont Donna M. , Wittwer Nicole L. , Ross David , D'Andrea Richard , Lavranos Tina C. 
Published: August 2018

BNC105 is a phase II potent and highly selective disruptor of tumor microvasculature that causes the rapid onset of hypoxia and necrosis in solid tumors. BNC105 targets the colchicine-binding site on tubulin, causing chronic disruption of adhesion molecules, and was developed to be best-in-class with high specificity to actively dividing cells. It has one of the largest therapeutic windows of its class and has been shown to have direct cytotoxic activity on tumor cells. It is this highly tumor-specific mechanism of action that has positioned BNC105 as a therapeutic with high potential in the hematologic cancer setting. Previous studies of BNC105 have shown that treatment with BNC105 results in the activation of c-Jun N-terminal kinase (JNK), phosphorylation of ATF2, and the induction of ATF3 and Noxa, leading to acute apoptosis in chronic lymphocytic leukemia (CLL) cells. These findings led to the commencement of a phase 1/2 trial of BNC105 in patients with CLL. The present study was designed to investigate the effect of BNC105 treatment on acute myeloid leukemia (AML), a disease that currently has limited treatment options. To assess the utility of BNC105 therapy in this setting, six AML cell lines representing different subtypes, including the high-risk FLT3-ITD subtype, were initially used in proliferation and cytotoxicity assays. The production of reactive oxygen species (ROS), cell cycle distribution and cell signaling by Western blot were all assessed after treatment. All tested AML cell lines were highly sensitive to treatment with BNC105 with an IC50=0.2nM to 1.3nM after 48 hours treatment. Analysis of apoptosis induction revealed cell line-specific effects; however, a consistent dose-dependent increase in phosphorylation of JNK was observed across all cell lines. AML patient samples obtained from the South Australian Cancer Research Biobank (SACRB) were exposed to BNC105 at clinically relevant doses for up to 72 hours and cellular viability and apoptosis induction were assessed by Annexin V/ 7AAD staining and caspase 3 and 7 activation measured. BNC105 induced caspase activity and significantly decreased viability in a dose- and time-dependent manner, including the FLT3 mutant subtype patient samples. In comparison, bone marrow mononuclear cells from healthy controls were much less affected by BNC105. Effects of BNC105 on the leukemic stem cell (LSC) phenotype population were also investigated. The LSC-containing population, measured by CD34/CD38 and GPR56 or CD93 staining, was targeted by BNC105 in all AML patient samples tested. These results suggest that AML cells can be directly targeted by BNC105 at clinically relevant concentrations and hence further clinical investigation of BNC105 is warranted for AML treatment in a patient population with high unmet need.

Citation Format: Daniel J. Inglis, Debora A. Casolari, Tran Nguyen, Donna M. Beaumont, Nicole L. Wittwer, David Ross, Richard D'Andrea, Tina C. Lavranos. The microtubule-disrupting drug BNC105 is a potent inducer of apoptosis in AML patient samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1881.