A team of researchers at the University of Michigan Rogel Cancer Center has found that a gene mutation can be used as an indicator for more effective treatments against brain tumors in young adults. These findings were recently published by Cell Reports and provide possibilities regarding how we may combat this disease going forward, with potential updates on what is being done now versus something new coming down the pipeline soon enough!
The Protein Coding Gene ATRX is mutated in just over half of high-grade glioma in young adult patients, most commonly found among teenagers and adults up until 40 years old. Though some studies have given hints as to why this occurs; many questions remain unanswered by researchers who cannot use medicines currently available on the market because they do not target mutations like these exclusively – leaving them without an answer for what causes these diseases or how we might be able to treat them once more. “We’re still learning why this type of cancer affects the population and how it affects the response to targeted therapies,” said Carl Koschmann, M.D., pediatric neuro-oncologist at U -M Rogel Cancer Center in Ann Arbor who also works closely with Michigan’s Chad Carr Pediatric Brain Tumor center for research purposes on studying these types cancers.
Output: “It’s amazing what we’ve learned so far about children being affected by brain tumors! We are just now understanding more than ever before when they should have their first surgery or treatment plan put into motion.”
Glioma cells with mutations in ATRX have less amount and activity of Chk1, which is responsible for regulating cell division. “It’s a puppeteer protein,” said Dr. Koschmann “When you don’t have enough Chkisses Prison Break’ll happen.”
With ATRX-mutated cells, radiation causes more harm than good. These tumors don’t have the same checks in place to limit damage and so are much less able to deal with it when compared to healthy or gliomatous varieties
As you can see from this passage on page 362 about DNA repair within our bodies – “radiation generally stops cells cycling”. When Chk1 is silenced, cells can survive more radiation. This discovery could lead to a better understanding of how cancer treatment works and improve survival rates for people diagnosed with childhood acute lymphoblastic leukemia (ALL).
With this information, the team investigated how radiation sensitizers would interact with ATRX-mutant cells and target their unique biology.
In a study by Koschmann and colleagues in the Castro-Lowenstein Lab, they found that radiation was an effective treatment for glioma patients with mutations of ATRX. The researchers postulated that incorporating ATM inhibitors which prevented Chk2 from compensating for inactive Chk1 would increase efficacy against mouse samples–and sure enough, their tests showed this to be true!
The ATM inhibitors gave researchers a triple the survival rate for glioma patients, but only when it came to those who had mutations in their ATRX gene. The wild-type strain did not show this effect and instead seemed more susceptible with standard radiation therapy alone as opposed to combinations of drugs like temozolomide or radiotherapy plus chemotherapy (which are used together).
The blood-brain barrier is a difficult obstacle to overcome in treating brain tumors, but researchers are determined. “We were surprised by how well this kind of drug went into the tumor and did what we needed it to,” says Dr. Koschmann with his team’s investigation surrounding ATM inhibitors focused on figuring out if they could penetrate through such a railway blockage.
This team’s research shows that a specific class of drugs might help patients with glioma whose tumors have been found to contain an important mutation. “While we conducted our study in the lab using mice,” says Dr. Raha total about their finding, “we’re hopeful these findings will be relevant outside also.”
We have been in contact with the manufacturer of ATM inhibitors used for this research, and they are willing to work with us on our next steps. One trial currently underway uses AZD1390 but may exclude patients most likely mutationally equipped ATRX carriers who would be interested in participating if there was another option available!
“We’re hopeful that the trial sponsor will either start a new one or add an arm to their current study because we think these patients would have the best response,” said Koschmann.
The success of this study lies in the collaboration between him and his fellow researchers.
“The Rogel Cancer Center is a perfect place for me because it brings together people from different areas of cancer research,” says Durdivelevic. “I work with pediatric neuro-oncologists, radiation oncologists, and pathologists who study brain tumors.”
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