Targeting the cellular metabolic processes in Acute Myeloid Leukemia: A promising novel approach in cancer treatment

In order for cancer cells to grow and proliferate, cellular metabolic reprogramming must occur. The non-essential amino acid glutamine (Gln) has been implicated in facilitating this process. Consequently, the inhibition of this amino acid provides a clear target for cancer therapy. Furthermore, P. Matre et al. state that the targeting of metabolic processes has emerged as a novel, promising approach in cancer treatment.

Matre et al. from the University of Texas MD Anderson Cancer Center, Houston, TX, USA, investigated the role of the Gln utilization pathway in Acute Myeloid Leukemia (AML) cell lines and primary AML samples. Furthermore, this study involved determining the anti-AML efficacy of a novel orally bioavailable Glutaminase (GLS) inhibitor CB-839. The study was published in Oncotarget in October 2016.

Their key findings demonstrated the following:

• A subset of AML cell lines and primary AML cells were sensitive to Gln deprivation and to inhibition of GLS.
• Gln deprivation in cell lines resulted in (>60%) decreases in viable cell numbers and induced apoptosis.
• CB-839 induced metabolic changes in IDH1/2 mutant AML patient samples.
• CB-839 induced myeloid differentiation.

In summary, the authors reported that, despite the exploratory nature of this study, the results provide a rationale for the targeting of Gln metabolism with GLS inhibitors in AML treatment. This study is particularly promising as the novel agent demonstrated activity against IDH1 mutations which are driver mutations in AML.   These results also provide a potential novel therapeutic approach where combination therapy with standard and targeted agents could be employed.

Abstract

Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC). We analyzed mRNA expression of GLS1 splicing variants, GAC and KGA, in several large AML datasets and identified increased levels of expression in AML patients with complex cytogenetics and within specific molecular subsets. Inhibition of glutaminase by allosteric GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells. In cell lines and patient samples harboring IDH1/IDH2 (Isocitrate dehydrogenase 1 and 2) mutations, CB-839 reduced production of oncometabolite 2-hydroxyglutarate, inducing differentiation. These findings indicate potential utility of glutaminase inhibitors in AML therapy, which can inhibit cell growth, induce apoptosis and/or differentiation in specific leukemia subtypes.