Lab mouse
A 3-drug combination has demonstrated long-term efficacy against acute lymphoblastic leukemia (ALL) in mice, according to research published in Nature Communications.
Researchers found that when the production of nucleotides is stopped, a DNA replication stress response is activated, and this allows ALL cells to survive.
The team used these findings to devise a 3-drug regimen that blocks both of the nucleotide biosynthetic pathways and inhibits the replication stress response.
One of the drugs is triapine (3-AP), which inhibits ribonucleotide reductase (RNR) and enhances salvage nucleotide biosynthesis.
Another drug is DI-82, which inhibits the nucleoside salvage kinase deoxycytidine kinase (dCK).
And the third drug is VE-822, which inhibits the replication stress-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR).
The researchers tested these 3 drugs in a mouse model of pre-B-ALL. Starting on day 7 after inoculation of pre-B-ALL, the mice received 3-AP and DI-82 twice a day and VE-822 once a day.
The team said mice in the control group succumbed to their disease within 17 days. However, all of the mice that received the 3-drug combination were still disease-free 442 days after they had stopped treatment (on day 42).
The researchers said the combination was well-tolerated, as mice maintained their body weight and enjoyed long-term survival without any detectable pathology.
The team also tested a dosing regimen in which all 3 drugs were given once a day.
Although this was less effective than the first regimen, 4 of 5 mice had no detectable disease 313 days after stopping treatment.
Two of the researchers involved in this study are co-founders and equity holders of Trethera Corp, a company developing a dCK inhibitor known as TRE-515.
The University of California (where most of the study authors work) has patented intellectual property for small-molecule dCK inhibitors, and it was licensed by Trethera.
