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Dr. Herranz is a co-corresponding author of the work, along with Joshua D. Rabinowitz, MD, PhD, director of the Metabolomics Shared Resource and a research member in the Cancer Metabolism and Growth Program at Rutgers Cancer Institute of New Jersey and a professor in the Department of Chemistry and the Lewis-Sigler Institute for Integrative Genomics at Princeton University.
Herranz, who is also a member of the Cancer Pharmacology Program at Rutgers Cancer Institute and an assistant professor of pharmacology at Rutgers Robert Wood Johnson Medical School, shares more about the work published in the May 7 online edition of Leukemia (https://doi.org/10.1038/s41375-020-0845-6).
Why is this topic important?
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that affects both children and adults. Nowadays, most cases get cured by using intensive chemotherapy regimens, however, 20 to 50 percent of patients still relapse and, at this point, are refractory to current treatments and ultimately die of their disease. Thus, identifying novel therapeutic strategies for the treatment of T-ALL is of the utmost importance.
How was the study structured and what did you and your colleagues find?
Here, we described the first inhibitor of a particular enzyme (SHMT) with good chemical properties for its use in vivo. This enzyme plays a role in the one-carbon pathway, which is very important for T-ALL cells. Indeed, a drug that has been used in T-ALL for decades (methotrexate) also affects this same one-carbon pathway, but in the case of methotrexate by inhibiting a different enzyme in the pathway.
What are the implications of these findings?
We provide evidence that the SHMT inhibitor shows strong anti-leukemic effects in mice in vivo as a single agent but, in addition, it also synergizes with methotrexate. Moreover, we found that leukemia cells that are resistant to Methotrexate are even more sensitive to SHMT inhibition. Thus, our results offer a new therapeutic strategy for the treatment of T-ALL, which can be particularly effective in cases that are refractory to Methotrexate.
What are future steps pertaining to this work?
Additional studies down the line should elucidate whether SHMT inhibition might synergize with other drugs currently used in the treatment of T-ALL or whether treatment with this drug uncovers novel vulnerabilities in leukemic cells. Even more important, clinical trials in T-ALL patients in the short/mid-term should demonstrate the efficacy of SHMT inhibition in this disease.
Author acknowledgements, disclosures and other information can be found here.
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