It may possible to combat acute lymphoblastic leukemia (ALL) with a new three-drug combination. Researchers at University of California Los Angeles (UCLA) are reporting that they have come up with a new approach that could eventually help young patients with ALL better respond to treatment. The scientists report in the journal Nature Communications that they have discovered shutting down the production of nucleotides activates a DNA replication stress response.
The replication stress response is a cellular monitoring system that usually senses and resolves DNA damage. Now it appears there may be a way to manipulate the replication stress response to disarm ALL in a novel way. Lead study author Caius Radu, MD, a professor in the department of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, said every time there is a slowdown in DNA replication it is defined as replication stress.
“We can induce replication stress and cripple the coping. It is like financial stress when someone is spending too much money. We are giving them even more credit cards,” Dr. Radu told OncoTherapy Network. “We are jamming the breaks. We are preventing them from applying the breaks. They run a deficit and they lack building blocks and then they crash.”
He and his colleagues have devised a three-drug combination treatment regimen that was able to eradicate ALL in mouse models. The three-drug combination was able to block both of the nucleotide biosynthetic pathways and inhibit the replication stress response.
The authors write that leukemia cells rely on two nucleotide biosynthetic pathways (de novo and salvage). These pathways produce deoxyribonucleotide triphosphates. The researchers theorize that metabolomic, proteomic, and phosphoproteomic approaches may be able to inhibit the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR). This may subsequently reduce the output of both de novo and salvage pathways.
Two of the experimental drugs, triapine (3-AP) and DI-82, were used to lower nucleotide levels. The third drug (VE-822) inhibited ATR. The researchers then noticed that VE-822 disabled the brakes applied by the replication stress response and allowed the three-drug combination to kill lymphoblastic leukemia cells.
The authors also note that this three-drug combo was shown to promote long-term survival of treated animals without causing toxicity after only a short duration of treatment. This study builds and improves upon previous work investigating how lymphoblastic leukemia cells produce nucleotides.
Mouse models were used in the preclinical research to assess the effectiveness of the three-drug combination over a 4-year period. The next stage of research tests the individual components of the combination therapy in clinical trials. At least one phase I trial is set to begin before the end of the year.
Dr. Radu and his colleagues report that functional interplay between alternative nucleotide biosynthetic routes and ATR may provide new therapeutic opportunities not only for leukemia but for other cancers as well. “Current treatments are so toxic and this could be significantly different,” explained Dr. Radu.