"Possible drug target" Identification of a gene normally restricted to the testis, which is active in 70% of cancers.

Scientists have found that a gene called FOXR2, which normally does not function in most body tissues, is activated in at least 70% of cancers and 8% of all individual types of tumors.

The results of this study, recently published in the journal Cancer Research, could help scientists better understand how different types of cancer develop.

A research team from MIT’s Broad Institute, Harvard University and the Dana-Farber Cancer Institute is working with chemists and structural biologists to figure out how to target this gene with potential new treatments.

“The fact that this gene is usually turned off in most tissues means we can target it in a way that doesn’t cause many side effects,” said lead researcher Pratiti Bandupadi, an associate member of the Broad Institute and a pediatrician. neuro-oncologist at the Dana-Farber Institute.


Jessica Tsai, a pediatric oncologist at Dana-Farber, a postdoctoral fellow in Bandupaddaya’s lab and first author of a scientific paper, was sequencing the genome of a type of childhood brain cancer called metastatic gliomas — deadly midbrain tumors — when, surprisingly, she and her team found that many cancers show abnormal expression of FOXR2. This gene encodes a transcription factor, is located on the X chromosome and is normally expressed only in the testes.

To figure out the effect of the gene on other cancers, Tsai and her colleagues scanned cancer databases, analyzed human cell cultures, and sequenced tumors in animal models of cancer. They found that some of the most common childhood and adult cancers, including osteosarcoma, melanoma, and non-small cell lung cancer, also show FOXR2 expression, as well as metastatic gliomas in the midline Dana-Farber Tumor Bank. The team collaborated with David Jones of the German Cancer Research Center to confirm that many childhood tumors act on FOXR2.

“The families that donated these tumors really allowed us to look at genes like FOXR2 and describe their role in these devastating brain tumors,” said Bandupadhyayi.

Function hints

Working with Tim Phoenix of the University of Cincinnati, the scientists studied mice with and without FOXR2 activation and found that gene expression increased the growth rate of brain tumors, including metastatic gliomas.

They also found that cells turn on the gene through a process called hypomethylation, a chemical modification that removes methyl groups from the gene. The researchers found that a group of transcription factors called ETS are overexpressed when FOXR2 is active, which can lead to tumor formation.

The team suspects FOXR2 may be part of a larger pattern in which normally inactive testicular genes are turned on in cancer patients.

Other studies have shown that proteins encoded by genes on the X chromosome, called testicular cancer antigens, are abnormally expressed in tumors. These antigens have been a prime target for drug manufacturers developing new cancer treatments.

The scientists say their study provides some early clues about how FOXR2 works, but there is still much more to learn.

The team hopes to unravel the relationship between ETS and FOXR2 to better understand how the gene is activated. The team has also already collaborated with other labs at the Broad Cancer Institute and Dana-Farber to explore how to develop cancer therapies that target FOXR2.

Source: Medical Express