HomeLifestyleHealth & FitnessThis new research may help develop a new treatment for Ovarian cancer

This new research may help develop a new treatment for Ovarian cancer

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A new study published in the journal Oncogenesis and led by researchers at the University of Alabama at Birmingham discovered that a gene called DOT1L appears to play a role in the progression and severity of ovarian cancer, and that inhibitors of the DOT1L enzyme may offer a new treatment option for the disease.

Despite decades of research, the five-year survival rate for advanced ovarian cancer patients is between 10 and 30 percent.

The team, led by Romi Gupta, Ph.D., assistant professor of biochemistry and molecular genetics, have now demonstrated that DOT1L promotes ovarian cancer growth by activating pro-tumorigenic metabolic pathways and inhibiting apoptosis, a type of programmed cell death.

Gupta and colleagues began by examining patient data sets. They discovered that DOT1L expression was significantly higher in ovarian cancer patients’ tissues than in healthy patients’ tissues. Additionally, patients with high DOT1L expression in their ovarian tumors had shorter progression-free survival and a shorter overall survival rate compared to patients with low DOT1L expression in their ovarian tumours.

DOT1L is a histone methyltransferase that alters the histone H3 lysine 79 in chromatin epigenetically, thereby altering gene expression in cells. EPZ-5676 – a DOT1L inhibitor that has been used in several clinical trials to treat MLL-rearranged leukaemia – was found to be capable of inhibiting the growth of ovarian cancer cells in culture, the UAB researchers discovered. Additionally, EPZ-5676 significantly inhibited the growth of subcutaneous ovarian cancer tumours in a mouse xenograft model.

Mechanistically, DOT1L inhibition downregulated the expression of various genes that are required for biosynthetic pathways and reduced the levels of essential biosynthetic metabolites in ovarian cancer cells. DOT1L inhibition also upregulated genes involved in programmed cell death, which increased apoptotic cell death for ovarian cancer cells in culture. The pharmacologic inhibition of DOT1L also upregulated expression of ligands for natural killer cells in some of the ovarian cancer cell lines tested.

These changes in gene expression observed in cells treated with DOT1L inhibitors suggest that overexpression of DOT1L in ovarian cancer results in an abundance of the metabolites required for rapid tumour growth and also protects against tumor cell death caused by apoptosis or natural killer cell attack.

“Our results suggest that DOT1L might be a pharmacologically tractable drug target for ovarian cancer therapy,” Gupta said.

“It will also be useful in combination with other immunotherapeutic agents to further enhance their effectiveness in treating ovarian cancer.”

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