Abstract 3075: Anti-leukemic activity of BCL-2/BCL-XL dual inhibitor - AZD0466 in T-acute lymphoblastic leukemia preclinical models
Authors: Kannan Sankaranarayanan , Ghotbaldini Sanaz , Wells Julia E. , Zhang Qi , Balachander Srividya , Cidado Justin , Konopleva Marina 
Published: September 2020

Abstract
Upregulation of BCL-2 family proteins, such as BCL-2 and BCL-XL, leads to imbalanced ratio between pro-death and pro-survival proteins that favors leukemic survival, tumorigenesis, and is an important driver of chemoresistance. B- and T-ALL JAK-STAT signaling pathway is positively correlated with increased BCL-2 family function. Importantly, this pathway plays an important role in the switch between BCL-2 and BCL-XL dependencies in normal developing T-cells. However, recent studies have shown that co-expression of BCL-2 and BCL-XL is linked with higher therapeutic resistance in different types of ALL. In this study, we tested BCL-2 and BCL-XL dependencies among different subtypes of ALL and the potential to revert these using AZD0466, a novel drug-dendrimer conjugate, of a BCL-2/ BCL-XL inhibitor AZD4320 and an FDA-approved BCL-2 inhibitor, ABT-199 (Venetoclax). The analysis of protein expression patterns in ALL cell lines revealed increased levels of BCL-2 in B-ALL cell lines, and of BCL-XL in Ph-like B-ALL and T-ALL cell lines. The analysis of cell viability assay revealed most B-ALL cell lines show sensitivity to both ABT-199 and AZD4320, except NALM6 which lacks the expression of the executioner Bax protein. Ph-like B-ALL and T-ALL cell lines on the other hand are most sensitive to the BCL-2/BCL-XL dual inhibitor, AZD4320. Additionally, Ph-like B-ALL and T-ALL PDX cells responded greater to dual inhibitor. The analysis of BH3 profiling of ALL cell lines demonstrated BCL-2 and BCL-XL codependence in Ph-like B-ALL and T-ALL cell lines while major BCL-2 dependence was seen in B-ALL cell lines. Our pre-clinical studies in T-ALL PDX models showed moderate response to ABT-199 and significantly prolonged survival and decreased leukemic burden mice treated with dual BCL-2/BCL-XL inhibitor AZD0466 (30mg/kg/weekly/IV). Importantly, AZD0466 treated cohorts did not show any significant change in the body weight and platelet counts when compared to control animals. Comparison of pharmacological response to dual inhibitor AZD0466 treatments in B-ALL PDX models demonstrated lower therapeutic efficacy than observed in T-ALL PDX, while in the same T-ALL PDX ABT-199 (100mg/kg/daily/oral) showed reduced efficacy. Further studies including BH3 profiling to measure the dynamic response of mitochondria and determine prior BH3 domain dependencies are in progress and will be reported. Our findings suggest that the novel dual BCL-2/BCL-XL inhibitor AZD0466 outperforms single BCL-2 inhibition by ABT-199 in T-ALL and Ph-like B-ALL. These findings will facilitate translation of AZD0466 dual BCL-2/BCL-XL inhibitor into ALL clinical trials, alone or in combination with standard chemotherapy and monoclonal antibodies.
Citation Format: Sankaranarayanan Kannan, Sanaz Ghotbaldini, Julia E. Wells, Qi Zhang, Srividya Balachander, Justin Cidado, Marina Konopleva. Anti-leukemic activity of BCL-2/BCL-XL dual inhibitor - AZD0466 in T-acute lymphoblastic leukemia preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3075.