Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Translational Research, Combination therapy, Diseases, Therapies, Myeloid Malignancies
AML patients with TP53 mutations are known to have lower response rates to venetoclax. The in vivo efficacy of HC-7366 in both CDX and PDX models was independent of TP53 mutation, resulting in 100% complete response and 100% tumor growth inhibition in TP53-mutated MOLM-16 and KG-1 tumor models, respectively. Analysis of tumors from treated mice by IHC demonstrated activation of the ISR as evidenced by increased expression of the ATF4 targets ASNS and PSAT1. A genome-wide CRISPR screen in KG-1 cells revealed that GCN2 sgRNAs were significantly enriched in HC-7366-treated cells, highlighting the importance of GCN2 activation in mediating the mechanism of action of HC-7366. Interestingly, BCL2 sgRNAs were significantly depleted in HC-7366 treated cells, suggesting a synthetic lethal relationship with BCL2 inhibitors, such as venetoclax, when combined with HC-7366. Indeed, in the MV4-11 FLT3-ITD mutant model (a differentiated subtype of AML that shows limited response to venetoclax), the combination of HC-7366 and venetoclax produced substantial benefit resulting in 26% tumor regression and enhanced activation of the ISR pathway. HC-7366 treatment also increased mRNA and protein levels of NOXA and PUMA while reducing mitochondrial respiration and glycolysis in a GCN2-dependent manner, leading to a low energetic state. Consistent with its impact on cellular energetics, global metabolomic analyses of AML xenograft tumors showed that HC-7366 significantly altered metabolites associated with glycolysis and the TCA cycle. Additionally, HC-7366 reduced protein levels of S100A8/A9, also known to correlate with venetoclax resistance.
Our in vitro and in vivo results demonstrate that HC-7366 is a potent GCN2 activator with strong antitumor activity in AML as a single agent and in combination with venetoclax. The potential of HC-7366 to counteract multiple known resistance mechanisms to venetoclax could provide a viable treatment option for patients with relapsed/refractory AML when used in combination with venetoclax.
Disclosures: Tameire: HiberCell Inc.: Current Employment, Current equity holder in private company. Collette: HiberCell Inc.: Current Employment, Current equity holder in private company. Fujisawaa: HiberCell Inc.: Current Employment, Current equity holder in private company. Bieging-Rolett: HiberCell Inc.: Current Employment, Current equity holder in private company. Dudgeon: HiberCell Inc.: Current Employment, Current equity holder in private company. Stokes: HiberCell Inc.: Current Employment, Current equity holder in private company. Harrison: HiberCell Inc.: Current Employment, Current equity holder in private company. LaCayo: HiberCell Inc.: Current Employment, Current equity holder in private company. Wojnarowicz: HiberCell Inc.: Ended employment in the past 24 months; Congruence Therapeutics: Current Employment. Drees: HiberCell Inc.: Current Employment, Current equity holder in private company. Staschke: HiberCell Inc.: Consultancy, Research Funding. Surguladze: HiberCell Inc.: Current Employment, Current equity holder in private company. Lightcap: HiberCell Inc.: Current Employment, Current equity holder in private company. Bose: HiberCell Inc.: Current Employment, Current equity holder in private company.