Approximately 12,000 new patients of AML are diagnosed each year and 9,000 die due to AML relapse and/or toxicity of the therapy. There is an unmet need to develop novel, targeted and safer therapies for AML. Of all adult AML, approximately 50% have normal karyotype (NK) and one-third of these express FLT3 with internal tandem duplication (ITD), which is associated with a poor clinical outcome. AML stem/early progenitor cells are capable of limitless self-renewal and proliferation, and are relatively treatment-refractory. The canonical WNT- ?-catenin pathway is essential for self-renewal, growth and survival of AML stem/progenitor cells. In AML, deregulated WNT signaling inhibits degradation of ?-catenin, causing increased nuclear localization and interaction of ?-catenin with the bipartite TCF/LEF transcription factor. This results in up regulation of genes involved in the growth and survival of AML stem/progenitor cells. An adaptor protein TBL1 (Transducin ?-like protein 1) is required for ?-catenin mediated transcription of target genes that promote the AML phenotype. Our preliminary studies demonstrate that BC2059 (?-Cat Pharmaceuticals), a novel, small molecule, anthraquinone oxime-analog, potently disrupts the binding of TBL1 with ?-catenin, promoting the proteasomal degradation ?-catenin. This represents a novel and innovative approach to attenuate the nuclear levels and transcriptional activity of ?-catenin. Our preliminary findings also demonstrate that BC2059 exerts in vitro and in vivo anti-AML activity against cultured and primary human NK-AML blast progenitor cells (BPCs), including those expressing FLT3-ITD, without inducing host toxicity. Additionally, our preliminary studies show that co- treatment with the histone deacetylase inhibitor (HDI) panobinostat (PS) or FLT3 antagonist AC-220 enhances BC2059-induced apoptosis of human AML BPCs. Therefore, we propose to test the hypothesis that BC2059 mediated knockdown of ?-catenin levels/activity would synergistically interact with a histone deacetylase inhibitor (HDI) or FLT3 antagonist in exerting anti-AML efficacy against AML with or without (w/wo) FLT3-ITD.
The aims of the proposal are:
AIM 1 : To further elucidate the in vitro growth inhibitory, differentiation and apoptotic effects of BC2059, and the underlying mechanisms, in cultured and primary human AML BPCs, as well as evaluate the in vivo efficacy of BC2059 against established human AML in mouse models.
AIM 2 : To determine the in vitro and in vivo efficacy of co-treatment with BC2059 and HDI against human AML BPCs.
AIM 3 : To determine the in vitro and in vivo anti-AML efficacy of BC2059 and a FLT3 antagonist against cultured and primary human AML BPCs expressing FLT3-ITD. These pre-clinical studies will generate the supportive in vitro and in vivo data as proof-of-concept for the clinical translation of BC2059-based therapy for AML w/wo FLT3-ITD expression.
Studies proposed here would further elucidate how BC2059, a novel small molecule inhibitor, reduces the levels and activity of ?-catenin and induces death of AML blast progenitor cells (BPCs) with or without the expression of mutant FLT3-ITD. The in vitro activity of BC2059 and/or the histone deacetylase inhibitors panobinostat and entinostat or the FLT3 antagonist AC220 will also be determined. Finally, the in vivo efficacy of BC2059-based combinations with HDIs and AC220 will also be determined utilizing NSG mouse model of established human AML caused by AML BPCs with FLT3-ITD expression.
|Saenz, D T; Fiskus, W; Qian, Y et al. (2017) Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia 31:1951-1961|
|Devaraj, S G T; Fiskus, W; Shah, B et al. (2016) HEXIM1 induction is mechanistically involved in mediating anti-AML activity of BET protein bromodomain antagonist. Leukemia 30:504-8|
|Fiskus, W; Sharma, S; Saha, S et al. (2015) Pre-clinical efficacy of combined therapy with novel ?-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells. Leukemia 29:1267-78|
|Fiskus, W; Sharma, S; Shah, B et al. (2014) Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia 28:2155-64|