Targeting DNA Repair Pathways to Treat Brain Tumors

Researchers in Japan have analyzed the chromosomes of brain tumors and found an inhibitor molecule that could be utilized as a part of the treatment of childhood brain cancer.

In a study published in the Journal of National Care Institute, researchers in Japan have examined the chromosomal deformities that happen in childhood brain cancer and identified an inhibitor that could be utilized to treat brain tumors.

Neuroblastoma (NB) is the most widely recognized solid tumor found in children. Immature nerve cells typically found in the embryo or fetus is responsible for the development of these brain tumors. A few genome changes in NB have been reported for the deletion of the long arm of chromosome 11 (11q deletion) is one of the most frequent events in aggressive NB.

In the past two decades, in spite of extensive efforts to identify the genes related to 11q aberrations in NB, definitive answers are still unclear. Prior examinations have featured the significance of the DNA damage response (DDR) in NB.

In this examination, scientists at the Tokyo Medical and Dental University (TMDU) researched the role of the gene ATM and DDR-related molecules located in 11q.

“The protein ATM, encoded by the ATM gene, is a master regulator of DDR crucial for the maintenance of genome integrity. When DNA damage occurs in genes in the DDR itself that play a crucial role, the checkpoint pathway is compromised, contributing to the development of cancer,” clarified Associate Professor Masatoshi Takagi of TMDU, who is the lead author of the examination.

“Among 237 fresh tumor tests from the patients, we discovered ATM, MRE11A, H2AFX, as well as CHEK1 gene loss or imbalance in 11q of every 20.7 percent of NB, 89.8 percent of which were stage 3 or 4 cancer.”

Furthermore, nearly half of the samples had either a single nucleotide variation, copy number alterations, or the two deformities in those genes.

ATM- defective cells are known to exhibit dysfunctional DNA repair, which led the analysts to hypothesize that poly (ADP-ribose) polymerase (PARP) inhibitors might be viable in capturing NB growth. Indeed, the group found that 83.3 percent of NB- derived cell lines were sensitive to PARP inhibition.

Takagi said, “There is substantially more to reveal such as how and when the mutation of DDR- associated molecules, or loss of 11q, occurs during tumor development and progression”.

“It will also be important to compare the frequency of mutations in DDR- associated molecules, or 11q misfortune, between initial samples and relapsed or metastatic samples. In any case, our present outcomes additionally support the inhibition of PARP as a promising therapeutic approach for particularly targeting on NB,” he included.


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