A diverse team of scientists from UCLA's Jonsson Comprehensive Cancer Center have developed an experimental treatment that eradicates an acute type of leukemia in mice without any detectable toxic side effects. The drug works by blocking two important metabolic pathways that the leukemia cells need to grow and spread.
The study, led by Dr. Caius Radu, associate professor of the biomedical physics interdepartmental program and molecular & medical pharmacology, and Dr. David Nathanson, assistant professor of molecular and medical pharmacology, was published online ahead of print on February 24, 2014 in the Journal of Experimental Medicine.
Metabolism is the inner workings of cells, and the many mechanisms and chemical reactions that maintain the cell and allow it to survive and reproduce by division. Elements of metabolism called biosynthetic pathways allow cells to synthesize chemicals, called nucleotides, that they need to survive. When these nucleotide pathways are blocked by drug molecules, cancer cell growth can be halted and cell death can be triggered.
Radu and Nathanson and their colleagues found that an important nucleotide called deoxycytidine triphosphate (dCTP) is produced by two pathways, the de novo pathway (DNP) and the nucleoside salvage pathway (NSP). When an existing drug was given that blocks the DNP in a leukemia cell, the dCTP nucleotide was still produced by the NSP and the leukemia cell survived.
To counter this switch to the alternative pathway, the researchers created a small-molecule drug called DI-39, which blocks the NSP. When both these drugs are given, both pathways are blocked with a one-two punch, the leukemia cells cannot produce dCTP nucleotides, and the cells die.
In this study, the two-pronged experimental treatment was given to mice that had acute lymphoblastic leukemia (ALL, a deadly blood cancer). The treatment eradicated the cancer cells, leaving healthy blood cells alone, and the mice suffered no detectable side effects.
"All cancer cells utilize these two pathways, and they have a strong avidity for these nucleotides to synthesize their DNA or repair it," Nathanson said. "Thus, we believe that this treatment strategy might be applicable across other hematological malignancies besides leukemia."
The small molecule drug used in this study was developed exclusively at UCLA.
"Usually people say that drug discovery and development cannot happen strictly in the academic environment, that discovery should be done in academia, and development done elsewhere, such as in industry," said Radu. "With this study we show that everything can be done in the academic environment. We started this project from scratch and with the help of UCLA scientists from many different disciplines, we have taken the drug through all the steps, nearly ready for clinical trials."
Among the study's many UCLA collaborators were Drs. Michael Phelps, Norton Simon Professor and chair of molecular & medical pharmacology; Michael Jung, distinguished professor of chemistry & biochemistry; Harvey Herschman, distinguished professor and vice chair of molecular and medical pharmacology and distinguished research professor of biological chemistry; Kym Faull, professor of psychiatry and biobehavioral sciences; and Johannes Czernin, director of the nuclear medicine clinic, positron emission tomography/computed cosmography (PET/CT) and professor of medicine.
This research was supported by the UCLA Scholars in Oncologic Molecular Imaging Program (SOMI), the Jonsson Comprehensive Cancer Center at UCLA, the National Cancer Institute and the National Institutes of Health.
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