NOVEMBER 12, 2019, New York— A study led by Ludwig MIT Co-director Tyler Jacks has identified a new therapeutic target for small cell lung cancer, an especially aggressive form of lung cancer that has a five-year survival rate of about 6%.
“Unfortunately, we haven’t seen the same kinds of new treatments for small cell lung cancer as we have for other lung tumors,” says Tyler Jacks, who is also director of the Koch Institute for Integrative Cancer Research at MIT. “In fact, patients are treated today more or less the same way they were treated 40 or 50 years ago, so clearly there is a great need for the development of new treatments.”
The study, reported in the Nov. 6 issue of Science Translational Medicine, shows that small cell lung cancer cells are especially reliant on the biochemical pathway for synthesizing pyrimidines, which are among the building blocks of DNA. The researchers also show that the drug brequinar, a pharmacologic inhibitor of an enzyme in that pathway that has been approved for clinical use, is effective against the disease in cell lines and mouse models.
Researchers in the Jacks lab used the genome editing tool CRISPR to screen small cell lung cancer cells for genes that already have drugs targeting them or are likely to be druggable.
They found that small cell lung cancer tumors are particularly sensitive to the loss of a gene encoding dihydroorotate dehydrogenase (DHODH), which is involved in pyrimidine biosynthesis. Working with the laboratory of Ludwig MIT researcher Matthew Vander Heiden, the investigators found that the pyrimidine synthesis pathway is much less active in small cell lung cancer cells than in several other types of cancer cells.
Treating a mouse model of small cell lung cancer with the DHODH inhibitor brequinar slowed tumor progression and extended survival of the mice. Similar results were observed for small cell lung cancer tumors in the liver, a frequent site of metastasis in patients.
The researchers also tested four patient-derived small cell lung cancer tumor models and found that brequinar worked well for two of these models—one of which does not respond to a standard treatment for this disease.
More detail about these findings is available in the MIT release from which this summary is derived.