Leukemia is a group of blood cancers that results in excess amounts of white blood cells. There are both chronic forms of leukemia that progress slowly over many years and acute types of leukemia that evolve rapidly. Acute myeloid leukemia (AML), one of the most common forms of blood cancer, affects more than 20,000 people in the United States each year, and the mortality rate is high especially in older patients. One of the most common drugs to treat AML is cytarabine (ara-C), a cytotoxic drug that interferes with DNA replication. However, many patients do not respond to it because their leukemic cells express high levels of the enzyme SAMHD1, which breaks down the active metabolite of cytarabine, ara-CTP. These patients have a significantly worse survival rate than patients with low leukemic levels of SAMHD1. Therefore, one promising strategy to improve the treatment of AML is to inhibit the effects of this enzyme on cytarabine. But a common and inexpensive drug may be used to counteract treatment resistance in patients with AML. This is the conclusion of a study in mice and human blood cells performed at Karolinska Institutet and SciLifeLab and published on EMBO Molecular Medicine.
In this study, the researchers tested the impact of more than 33,000 different substances on SAMHD1’s ability to break down ara-CTP in leukemia cells treated with cytarabine. The experiment led to the identification of three different substances, so-called ribonucleotide reductase inhibitors (RNRi), that all reduced SAMHD1’s ability to deactivate ara-CTP: hydroxyurea, gemcitabine and triapine. Hydroxyurea is an inexpensive drug that is used to treat blood diseases such as AML and sickle cell anemia. However, it has not systematically been used in combination with cytarabine. Gemcitabine is a potent drug that is used to treat many different types of cancers, but it can be toxic if given repeatedly. Triapine is a drug currently undergoing clinical studies for cancer treatment, from bladder to uterine cancer to some blood malignancies. In animal studies, the combination therapies did not exhibit any excess side-effects beyond those already established in cytarabine-treatments. The researchers were also able to show how the RNR-inhibitors affected the SAMHD1-levels mechanistically. These drugs change the intracellular composition of deoxynucleotides (dNTP), which are building blocks for nucleic acids.
Since SAMHD1 needs dNTPs to activate its enzymatic activity, this effectively abrogates its ability to break down ara-CTP. The research group is now planning to move forward with a clinical study that will evaluate the effect of combining standard AML-treatment with hydroxyurea in recently diagnosed patients. Nonetheless, a significant proportion of blood cancers in both adults and children remain resistant to current treatments and they lead to death. Another vulnerability discovered in certain subtypes of leukemia could be taken advantage of: the methionine-SAM axis. Methylation is a molecular switch for proteins and nucleic acids and many cellular methyl-transferases continuously modify cellular proteins in order to reach homeostasis. DNA stability is reached also by methylation events: not only DNA itself but core histones themselves are methylated to control genetic stability and espression. These phenomena seem particularly vulnerable in acute lymphoid (ALL) and myeloid (AML) leukemias, especially the subtypes bearing the MLL1 gene rearrangement, which account for 70–80% of infant leukemias and have a very poor prognosis.
In these cases, hitting methionine metabolism not only would deplete methyl groups for histone methylation (the DOT1L and KAT3 are the methyltransferases most involved), but would interfere with the SAM-folate crosslalk needed for DNA base synthesis as well. Importantly, the intracellular ratio of SAM:SAH dictates the overall methylation potential of the cell, and SAM levels must be maintained in sufficient excess compared to SAH for methylation reactions to proceed. Cytosine methylation on DNA actively control gene expression and in cancer cells the general concept admits that a wider gene demethylation is achieved in order to allow the expression of formerly silenced gene, that could controbute to neoplastic transformation. Once SAM metabolismi s impaired, the accumulation of downstream biosynthetic products like SAH inhibits cellular methylation reactions, including epigenetic methylation of DNA or histones, by impairing cellular methylation potential. Additionally, SAM also serves as the sole source of the propylamine moiety required for polyamine biosynthesis. The small molecules are absolutely needed for DNA synthesis by controlling enzymes (tRNA synthetases, DNA polymerases) and protein kinases (e.g. casein kinase II) all involved in cell replication.
On the other hand, teams in Buffalo and Sydney opened a new treatment opportunity for patients with currently incurable blood cancers by introducing a new drug candidate shown to be highly effective in preclinical models. The clinical drug candidate, labeled as OT-82, takes advantage of the discovery of an extremely high dependence of blood marrow malignancies on elevated levels of nicotinamide dinucleotide (NAD), an essential cofactor of multiple metabolic and stress cellular pathways. OT-82 inhibits one of the major enzymes responsible for NAD production and salvage in cancer cells, nicotinamide phosphoribosyl transferase (NAMPT). Moreover, NAD is the cofactor for sitruins (SIRTs), a class of enzymes involced in further regulation of energetic metabolism, but it is also the cofactor for CtBP1. This curious nuclear protein is a co-repressor for gene transcription but is also an enzyme as well having affinity for reduced NAD (NADH). Once bound with NADH, it undergoes a conformational change that allows it to dimerize and associate with its partner proteins and silence specific genes. Not serendipitously, CtBP1 is a partner of AML1/MDS1/EVI1, a protein chimera responsible for AML and other myelodisplastic syndromes.
Another modality to hit the nucleometabolic core of leukemic cells would be by interfering with pyrimidine synthesis. Inhibitors of dihydro-orotate dehydrogenase (DHODH), the last enzymatic step for uracile production have been developed and showed antibacterial (against malarial Plasmodium) and immunosuppressant actions (e.g. leflunomide). Scientists from University Hospital Center of Zagreb, Croatia, think that pyrimidine withdrawal could be a convenient strategy to kill leukemic cells. They employed AICAR, one of the intermediates in pyrimidine biosynthetic chain, to induce depletion of these bases. The subsequent cellular response has been activation of the ATR/Ckh1 kinase checkpoint, a signaling pathway activated by ionizing radiation. Thus, this strategy would trigger the onset of a “phantom” external irradiation which is tipically associated with a stop in DNA replication. Beside, AICAR is an endogenous activator of AMPK, a protein kinase that mimics cellular starving and is provided with tumor suppressor abilities. Scientists discovered that AICAR was capable of triggering differentiation in samples of bone marrow blasts cultured ex vivo that were resistant to retinoic acid (ATRA).
These effects were recapitulated by brequinar, a well-known DHODH inhibitor. AICAR-induced differentiation correlated with proliferation and sensitivity to DHODH inhibition and may represent a simple strategy to achieve the erasing of leukemic stem cells, taking advantage of their high nucleometabolic rate. Overall, furtherly understanding the metabolic profiles of leukemic clones, their subtypes and geno/metabotypes, could lead to the development of much needed remission-inducing personalized therapies for patients.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Rudd SG et al. EMBO Mol Med. 2020 Jan 17: e10419.
Oellerich T et al. Nat Commun. 2019 Aug; 10(1):3475.
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Dott. Gianfrancesco Cormaci
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