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Researchers at Temple University in Philadelphia have developed a molecule that could be used in new cancer treatments. This molecule acts on an epigenetic marker, CDK9, which inhibits the expression of certain tumor suppressor genes (GSTs, which prevent the runaway cell division responsible for cancer). By restoring the expression of these genes, it would allow the body to defend itself against the tumor.
Epigenetic factors and cancer
It has been known since the 1980s that cancer is the result of mutations or genetic alterations that cause abnormal cell proliferation within healthy tissue. But for ten years, we also know that this is a disease as epigenetic as genetic. The epigenetic changes are not about the DNA of the cells themselves, but about how they transcribe and express it in their metabolism. These changes are transmitted during mitosis and also meiosis. However, by altering the expression of genes involved in cellular regulation, epigenetic modifications play an important role in the development of tumors.
Cellular regulation involves methylation (a chemical modification of the cytosine, the DNA base C) of the promoters of certain genes, which causes the latter not to express themselves, while others, unmethylated, express themselves. More simply, it relies on the inhibition of certain genes and the activation of others. In cancer, epigenetic markers act in two ways. Either they induce a methylation deficiency, which has the effect of activating the expression of proto-oncogenes or of allowing the abnormal expression of repetitive sequences of the DNA. Either they induce aberrant hypermethylation and thus the inhibition of genes such as GSTs. This last case is that of the CDK9 marker targeted by the study of Temple University researchers who discovered it.
Inhibiting epigenetic markers to treat cancer
By counteracting the perverse effect of these epigenetic markers, we could therefore fight cancer effectively, and create alternatives to chemotherapy. Instead of destroying the tumor cells, it would be a question of modifying their gene expression profile, and of reviving the body's natural defenses against tumors. Many studies have been conducted or are underway to develop epigenetic markers inhibitors. Some are already marketed, such as azacitidine (Vidaza), used in the treatment of certain leukemias. The molecule developed by the team of Jean-Claude Issa fits into this framework.
The researchers, after identifying CDK9, developed and tested a molecule capable of inhibiting it: MC180295. This highly targeted drug causes few side effects compared to chemotherapy. In vitro and mouse tests gave good results. Inhibition of CDK9 also allows a better immune response of the body to cancer in the mice tested.
There is more to hope that this molecule will prove effective in tests on humans. So far, epigenetic-based drugs have been shown to be more effective on leukemias and lymphomas than on solid tumors.
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