Aggressive drug changes epigenome in brain t

A folic acid-like drug, L-methylfolate, when given at the same time as standard treatment for patients with recurrent glioblastoma, altered the DNA process in their brain tumors, according to the findings of ” a phase 1 clinical trial.

Researchers have shown for the first time that methyloma DNA from these brain tumors can be reprogrammed. The study was published on January 5 in Cancer Research Communications. Stephen Clark, MD, PhD, neuro-oncologist at the Vanderbilt-Ingram Cancer Center, who is the study’s lead author and correspondent, said it was the first time that DNA methyloma reprogramming has taken place. produced with a solid human tumor.

DNA methylome is one aspect of the epigenome; epigenome is a modification of DNA and proteins in a cell that is influenced by the environment. DNA methylation is one such modification, where methyl groups are added to DNA and is a mechanism that controls gene expression, including the silencing or activation of genes linked to cancer. .

The researchers investigated whether remethylation of HDI wild-type tumors, which have a poorer prognosis and lower DNA methylation than mutant IDH tumors, could improve survival. They were successful in showing that the DNA methyloma of high-grade HDI wild-type gliomas could be reprogrammed, but the study group was too small to determine the impact on survival.

“This is an important first step in understanding how we can manipulate the epigenome and hopefully this study will help design future epigenetic studies in the treatment of glioblastoma,” said Clark, assistant professor of neurology. in the Division of Neuro-Oncology at Vanderbilt University. Center.

Although the study group of 14 patients was not large enough to detect a statistically significant survival advantage, patients treated with the folic acid supplement L-methylfolate had a median overall survival of 9.5 months, per compared to the typical median overall survival of 8.6 months. One of the patients is still alive.

The study provides a better understanding of the dynamics of epigenetic reprogramming, which is an emerging treatment to improve immunotherapies. In this Phase 1 clinical trial, researchers evaluated the response of patients receiving bevacizumab, a monoclonal antibody that prevents the growth and maintenance of tumor blood vessels, when treatment is augmented with L-methylfolate. The patients also received temozolomide, a chemotherapy drug. L-methylfolate was well tolerated and no toxicity was reported.

“Epigenetic reprogramming is not a new concept; for example, treatment with a DNA methyltransferase inhibitor (5-Azacytidine) has been studied and is approved for the treatment of certain leukemias. What is exciting about this work is that L-methylfolate works the opposite of 5-azacytidine; it increases the availability of active folate for DNA methyltransferases. Therefore, it could remethyl and repress genes activated during tumorigenesis, ”said study lead author Lucas Salas, MD, PhD, MPH, assistant professor of epidemiology at Dartmouth Geisel School of Medicine and researcher of the Cancer Population Sciences Research Program at the Norris Cotton Cancer Center in Dartmouth.

“In addition, we observed changes in the level of DNA methylation in tumors of people receiving L-methylfolate, suggesting that L-methylfolate not only crosses the blood-brain barrier, but it appears to actively modify the epigenetic landscape of the tumor. “

Six of the trial participants donated their brains upon death for further studies. Autopsies indicated a significant difference in methylation deregulation between these six autopsy samples and the patient’s initial tumor sample at the time of diagnosis.

The researchers plan to expand the study to include a larger group with a Phase 2 clinical trial of patients with recurrent glioblastoma. Future studies could also include combinations of epigenetic drugs with immunotherapy.

Clark and Brock Christensen, PhD, professor of epidemiology, community and family medicine, and molecular and systems biology at the Geisel School of Medicine in Dartmouth, co-supervised the study. Other contributors included Thomas Stewart, PhD, Bret Mobley, MD, Jing Liu, PhD, Sudan Loganathan, PhD, Jialiang Wang, PhD, and Paul Moots, MD, all of Vanderbilt; Chengwei Peng, MD, of Yale Medical School; Yanjun Ma, MD, PhD, of Tennessee Oncology; Mitchel Berger, MD, of the University of California at San Francisco; Devin Absher, PhD, of HudsonAlpha and Yang Hu, PhD, of CD Genomics.

The research was supported by the Barbara T. Russell Family Trust in Memory of Barbara Russell, the Stephen Voland Research Fund, grants from the National Institutes of Health, and Congressional / Department of Defense-led medical research programs.


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