Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster III
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, apoptosis, Translational Research, Combination therapy, Diseases, Therapies, Biological Processes, Myeloid Malignancies
NTX-301 greatly reduced the levels of DNMT1 and decreased viability in various AML cells, markedly more effective than 5-azacytide (5-Aza). NTX-301 decreased Mcl-1 and effectively induced cell death in AML cells overexpressing Mcl-1 and Bcl-2A1, both of which are upregulated by various kinases and resistant factors to venetoclax; in AML cells with intrinsic or acquired resistance to venetoclax; and in AML cells and stem/progenitor cells obtained from patients who were resistant/relapsed from venetoclax-based therapies. Furthermore, cell death induction in aforementioned cells was synergistically enhanced when NTX-301 was combined with venetoclax. NTX-301 alone or venetoclax/NTX-301 combination had minimal activity in normal bone marrow cells and bone marrow CD34+ stem/progenitor cells. Importantly, using a PDX model developed from an AML patient who relapsed from venetoclax/HMA, NTX-301 alone demonstrated great anti-leukemia activity and significantly extended survival (167 vs 114 days of control, P=0.0001), while venetoclax or venetoclax/5-Aza did not. CyTOF analysis of mouse bone marrow cells collected at the end of 5 week treatment showed that NTX-301 and even more so NTX-301/venetoclax effectively decreased CD45+ leukemia blast cells and CD34+CD38+/CD34+CD38- AML stem/progenitor cells, while venetoclax or venetoclax/5-Aza had not effects.
We observed that NTX-301 activated p53 in TP53 wild-type AML cells. We also observed that NTX-301 increased p73 and decreased MDM2 in TP53-mutant cells and showed activities in TP53-mutant leukemia cells. NTX-301 and venetoclax combination synergistically induced cell death and decreased viable cells in AML cells and stem/progenitor cells with TP53 mutations. Additionally, NTX-301 treatment increased caspase-8 and cleaved-caspase-8 in AML cells independent of TP53 mutation status, consistence with reports showing caspase-8 hypermethylation in AML and supporting that activation of caspase-8-mediated extrinsic apoptosis as a mechanism of NTX-301 action.
In conclusion, our data suggest that NTX-301 has more potent anti-leukemia activities compared to current HMA in clinic and synergizes with venetoclax in venetoclax-resistance and TP53-mutant AML and AML stem/progenitor cells, and warrants clinical evaluation
Disclosures: Carter: Syndax: Research Funding; PMV: Research Funding; Revolution Medicines: Research Funding; PinotBio: Research Funding. Shpall: Syena: Other: License agreement; Navan: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Axio: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: License agreement; Affimed: Other: License agreement; Celaid Therapeutics: Membership on an entity's Board of Directors or advisory committees; NY Blood Center: Membership on an entity's Board of Directors or advisory committees; Fibrobiologics: Membership on an entity's Board of Directors or advisory committees. Andreeff: PMV: Research Funding; Kintor Pharmaceutical: Research Funding.
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