Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a high mortality rate and relapse risk. Although progress on the genetic and molecular understanding of this disease has been made, the standard of care has changed minimally for the past 40 years and the five-year survival rate remains poor, warranting new treatment strategies. Here, we applied a two-step screening platform consisting of a primary cell viability screening and a secondary metabolomics-based phenotypic screening to find synergistic drug combinations to treat AML. A novel synergy between the oxidative phosphorylation inhibitor IACS-010759 and the FMS-like tyrosine kinase 3 (FLT3) inhibitor AC220 (quizartinib) was discovered in AML and then validated by ATP bioluminescence and apoptosis assays. In-depth stable isotope tracer metabolic flux analysis revealed that IACS-010759 and AC220 synergistically reduced glucose and glutamine enrichment in glycolysis and the TCA cycle, leading to impaired energy production and de novo nucleotide biosynthesis. In summary, we identified a novel drug combination, AC220 and IACS-010759, which synergistically inhibits cell growth in AML cells due to a major disruption of cell metabolism, regardless of FLT3 mutation status.
Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these combination therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 synergized with VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, an inhibitor of purine biosynthesis, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired resistance to AraC showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. These results translated into significantly prolonged survival upon combination of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.
SLC25A51 imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining oxidative metabolism in human mitochondria. We observed that higher expression of SLC25A51 correlated with poorer survival in Acute Myeloid Leukemia (AML) patient data. Given AML’s dependency on oxidative cell metabolism, we sought to determine the role SLC25A51 may serve in this disease. We found that depleting SLC25A51 in AML cells led to increased apoptosis, as well as prolonged survival in a xenograft model. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from oxidative pathways and promoted glutamine utilization for reductive carboxylation to support aspartate production. Consequently, SLC25A51 loss sensitized AML cells to glutamine deprivation and glutaminase inhibitor CB-839. Together, the work highlights connections between SLC25A51 and oxidative mitochondrial flux in AML. We identified a rationale for targeting SLC25A51 in myeloid cancers with potential for a therapeutic window, especially when coupled with glutaminase inhibition. Citation Format: Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu Cambronne. SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A42.
Purpose: Diet modulates gut microbiome composition and systemic inflammation—both intermediary factors in the development of colorectal neoplasia. We investigated the association of total dietary inflammatory potential, as assessed by the literature-derived dietary inflammatory index (DII®), with gut microbiota diversity and composition, microbial gene pathways, and circulating markers. Methods: This epidemiological study was comprised of 36 cancer-free colonoscopy patients (79% positive for precancerous polyps) and 65 healthy volunteers from the medical center community (N=101). Participants completed dietary assessments and provided stool samples for 16S rDNA sequencing >1 month after colonoscopy/polyp removal or antibiotic use. In a subset (n=47), we conducted whole genome shotgun (WGS) sequencing and collected a fasting blood sample. Energy-adjusted (E)-DII score was calculated for each subject and categorized into tertiles. The association between E-DII and fecal microbiota alpha- and beta-diversity was examined. Linear discriminant analysis Effect Size (LEfSe) was used to identify differentially abundant taxa by E-DII level. Multiple linear regression models were used to examine associations controlled for confounders. Results from the least absolute shrinkage and selection operator (LASSO) method and Spearman’s correlation were used to select and evaluate associations of bacterial species with E-DII, their functional pathways, and circulating markers. Results: We observed large between-person variation in Bacteroidaceae and Enterobacteriaceae, two dominant bacteria in the overall sample. Neither alpha- nor beta-diversity significantly differed across E-DII levels. Ruminococcus torques, Acidaminococcus intestine, and Clostridium leptum were most abundant in the most pro-inflammatory diet group, while Akkermansia muciniphila was enriched among subjects with the most anti-inflammatory diet. In the WGS subset, Luteimonas mephitis was inversely associated with E-DII, circulating Lipocalin-2 (r=-0.34; P=0.02), and plasminogen activator inhibitor-1 (r=-0.29; P=0.05). Akkermansia muciniphilaappeared to be inversely correlated with monocyte chemoattractant protein-1 (r=-0.26; P=0.09). Two microbial pathways inversely associated with E-DII, AMP-activated protein kinase (AMPK) and carbon metabolism, were also inversely correlated with C-peptide (AMPK: r=-0.35, P= 0.02; carbon: r=-0.30, P=0.04). Conclusions: Dietary inflammatory potential was associated with differential composition of specific microbes, but not overall diversity of the gut microbiome. Species associated with E-DII were similarly associated with circulating inflammatory biomarkers. Microbial AMPK signaling and carbon metabolism pathways may underlie diet-microbiota interactions that modulate systemic inflammation. Citation Format: Jiali Zheng, Kristi L. Hoffman, Nitin Shivappa, Jonathan Busquets, Jiun-Sheng Chen, Samir Hanash, Susan Schembre, James Hébert, Joseph Petrosino, Peng Wei, Carrie R. Daniel. Dietary inflammatory potential in relation to the gut microbiome among persons at varied risk of colorectal neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3320.
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