165438+ 10 is "Global Lung Cancer Concern Month". Recently, cancer biologists at the Massachusetts Institute of Technology have discovered a new target for the treatment of small cell lung cancer.
Tyler Jacks, director of the Koch Comprehensive Cancer Institute at MIT, said: "Regrettably, compared with the fourth-generation targeted drugs developed for non-small cell lung cancer, there are few new treatments for small cell lung cancer. The treatment of patients today is almost the same as that of forty or fifty years ago. Therefore, it is urgent to develop new treatments for small cell lung cancer. " In March this year, FDA approved Tecentriq combined with chemotherapy for the first-line treatment of adult extensive small cell lung cancer. This is also the only immunotherapy approved for small cell lung cancer. But immunotherapy is ineffective for some patients.
A recent study published in the journal Science Translational Medicine shows that small cell lung cancer cells are particularly dependent on pyrimidine biosynthesis pathway, and an enzyme inhibitor named Brequina has shown gratifying results in cell models and mouse models.
Stop cancer cells from dividing
Researchers in Jaxx Lab use CRISPR gene editing technology to screen cell models of small cell lung cancer, looking for genes with targeted drugs or potentially effective drugs, so as to find potential therapeutic targets and test them more quickly and conveniently in clinical environment.
The research team found that small cell lung cancer is particularly sensitive to the gene encoding dihydroorotate dehydrogenase (DHODH), which is a key enzyme in the biosynthesis pathway of de novo pyrimidine. After discovering that sensitivity involves metabolic pathways, the researchers collaborated with VanderHeidenLab. The laboratory is an expert in the metabolism of normal cells and cancer cells, and has been studying pyrimidine metabolism and the role of DHODH inhibitors in other cancers.
Pyrimidine is one of the main components of DNA and RNA. Unlike healthy cells, cancer cells are constantly dividing, and new DNA and RNA need to be synthesized to support the generation of new cells. The researchers found that small cell lung cancer cells are unexpectedly fragile: although they depend on the availability of pyrimidine, the activity of this synthetic pathway in small cell lung cancer cells is far lower than that of other types of cancer cells studied in the study. By inhibiting DHODH, they found that small cell lung cancer cells could not produce enough pyrimidine to meet the demand.
When researchers treated the genetically engineered mouse model of small cell lung cancer with DHODH inhibitor Breakey, the tumor progress slowed down and the survival time was longer. Similar results were observed for liver metastasis (common metastasis site) of small cell lung cancer.
In addition to the mouse model study, the researchers also tested the tumor models of four patients with small cell lung cancer, and found that Brequina had a good effect on two of them, and one of them was ineffective on the standard treatment scheme (platinum-etoposide).
Previously, for those patients with small cell lung cancer who failed first-line treatment, the choice of second-line treatment was very limited. In the future, these patients are expected to have new choices.
clinical trial
Brequina has been approved as an immunosuppressant, and some preclinical studies have shown that Brequina and other DHODH inhibitors may be effective against other cancer species.
It is reported that researchers are planning to conduct clinical trials of brequina as a treatment for small cell lung cancer to further verify its safety and effectiveness.
The researchers' next work includes optimizing the therapeutic effect of DHODH inhibitors and combining them with other treatments currently available for small cell lung cancer, such as chemotherapy and immunotherapy. In order to help clinicians tailor the treatment plan for patients, researchers will also determine the corresponding tumor biomarkers and study the mechanism of tumor resistance that does not respond to this treatment.
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