Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Research, AML, Acute Myeloid Malignancies, Combination therapy, Drug development, Translational Research, Diseases, Treatment Considerations, Myeloid Malignancies
We identified highly enriched stem-like populations overexpressing MYC in TP53 mutant AML samples compared to normal bone marrow and TP53 wild-type samples by single-cell RNA seq (Nishida et al. ASH 2023). Within CD34+ AML leukemia stem progenitor cells (LSPCs), MYC and Ki-67 protein levels, determined by single-cell mass cytometry, were elevated in CD34+CD38+ leukemia progenitors (LPs) and CD34+CD71+ megakaryoerythroid progenitors (MEPs) compared to CD34+CD38- leukemia stem cells (LSCs) or CD34- blasts in TP53 mutant AMLs, suggesting that LPs and MEPs, cell populations downstream from LSCs, utilize MYC for proliferation. Indeed, CD34+CD38+ LPs were more sensitive to GT19715 compared to CD34+CD38- LSCs in primary AML samples. Quiescent LSPCs exhibit sensitivity particularly to Venetoclax (Ven) (Zeng et al. Nat Med 2022), providing the hypothesis that the combinatorial approach of dual MYC/GSPT1 degradation with inhibition of BCL-2 targets both cell-kinetically active LPs and MEPs, and quiescent LSCs. Indeed, the combinatorial treatment of GT19715 with Ven/5’-azacitidine (Aza) exhibited synergistic cell kill (Bliss index 67.67, P = 2.11e-10) in CD34+CD38- LSCs in primary TP53 mutant AML samples (N = 7). The combinatorial treatment significantly prolonged survival of mice with PDX AML cells (PDX358) harboring TP53 p.Y220C and p.P151A compared to GT19715 or Ven/Aza monotherapy. Furthermore, GT19715 profoundly reduced AML blasts but spared CD34+CD38-CD71+CD235a+ AML cells. The combinatorial treatment nearly eradicated these remaining AML cells in bone marrow samples in another ongoing PDX AML experiment (PDX824) carrying TP53 p.Y220C and p.G105fs, suggesting that the combinatorial approach of dual MYC/GSPT1 degradation with Ven/Aza can be an effective therapeutic approach for TP53 mutant AML.
Conclusion: we identified a novel positive co-regulatory feedback loop between MYC and GSPT1, and found that dual MYC/GSPT1 degradation by GT19715 profoundly synergized in the induction of cell death in combination with Ven/Aza in both TP53 mutant quiescent and proliferating AML stem and progenitor cells.
Disclosures: Carter: Revolution Medicines: Research Funding; PinotBio: Research Funding; Ona Therapeutics: Research Funding; PMV Pharmaceuticals: Research Funding; Ellipses: Research Funding. Maiti: Hibercell Inc.: Research Funding; Chimeric Therapeutics: Research Funding; CytoMed Therapeutics: Research Funding; Lin Biosciences: Research Funding; Indapta Therapeutics: Research Funding; Inspirna: Research Funding. Ma: Oncobiotherapeutics: Current Employment. Andreeff: Boehringer-Ingelheim: Honoraria; Glycomimetics: Honoraria; Roivant: Honoraria; Oxford Biomedical: Research Funding; Paraza: Honoraria; Daiichi-Sankyo: Research Funding; Oncolyze: Current holder of stock options in a privately-held company; SentiBio: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Syndax: Honoraria, Research Funding; Ona: Honoraria; Aptose: Honoraria; Sellas: Honoraria, Research Funding; Kintor Pharmaceutical: Research Funding; Ellipses: Research Funding; Chimerix: Current holder of stock options in a privately-held company; Eterna: Current holder of stock options in a privately-held company, Honoraria, Research Funding.
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