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. Now 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 in the medical journal EMBO Molecular Medicine.
The study is the result of an international collaboration with researchers from Sweden, Germany, U.S., and South Korea and has also involved researchers at SciLifeLab, a national hub for molecular biosciences in Sweden. 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 deoxynucleoside triphosphates (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. The study will be conducted in collaboration with the Swedish AML-group and will begin recruiting patients within a few weeks. Nikolas Herold, researcher at the Department of Women’s and Children’s Health at Karolinska Institutet in Sweden, concluded: “Adding any of these three substances significantly improved the effect of the cytarabine-treatment in cell samples with high levels of SAMHD1. This was true for AML samples from both adults and children. Hydroxyurea is an approved drug that is already used to treat AML, so we think it has great potential. Beside, hydroxyurea is patent-free and doesn’t cost more than ibuprofen”.
Nonetheless, a significant proportion of blood cancers in both adults and children remain resistant to current treatments and they lead to death. The results of joint collaboration by teams in Buffalo and Sydney open 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. Yesterday, OncoTartis Inc. and Children’s Cancer Institute jointly announced the publication of two research manuscripts in a leading journal Leukemia, both devoted to the clinical drug candidate OT-82. The first paper describes the discovery, mechanism of action, toxicological profile and preclinical efficacy of OT-82, developed by OncoTartis for treatment of refractory leukemias and lymphomas. It 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, nicotinamide phosphoribosyl transferase (NAMPT). Its further clinical development is specifically focused on blood-derived cancers as the main disease target. OT-82 is currently undergoing a multicenter Phase I trial in the US.
The second paper on OT-82 describes a study conducted at Children’s Cancer Institute of Sydney. The Institute has been a world leader in establishing a large collection of refractory children’s leukemias grown in laboratory mice for new drug testing. These are widely accepted to be the most clinically-relevant models of childhood leukemia anywhere in the world. OT-82 demonstrated remarkable efficacy when used alone and was even more effective when used in combination with conventional treatments, thereby indicating promise for children with high risk blood cancers. Currently, OT-82 is being tested in a clinical trial of adults with relapsed or refractory lymphoma. Following the successful completion of this trial, it is anticipated that the drug will proceed to clinical trial in children with high-risk ALL. Professor Michelle Haber at Children’s Cancer Institute in Sydney, commented: “For children with particularly aggressive leukemia, the options for effective yet safe treatments are extremely limited and therefore novel therapeutic options are urgently needed. If OT-82 is found to be safe and effective in adults, we are very hopeful that it may provide an exciting new treatment approach for the worst cases of pediatric leukemia, with the added potential benefit of allowing reductions in doses of chemotherapy and hence side-effects”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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