Scientists discover potential drug candidates to treat brain tumors.

Clinical studies have shown that patients with diffuse midline glioma treated with ONC201 have prolonged survival; The study also explains the underlying mechanism behind the drug's success. For the first time, researchers have identified a potential drug candidate that promises to improve treatment outcomes for patients with a particular type of childhood brain tumor. The compound, known as ONC201, has been observed to nearly double the survival rate of patients diagnosed with diffuse midline glioma (DMG) or diffuse medial pontine glioma (DIPG).

University of Michigan Health Rogel Cancer Center and Chad Carr Pediatric Brain Tumor Center Center, an international team of researchers reported the findings.

In addition to reporting the results of two early-stage clinical trials, the paper reveals the underlying mechanisms underlying the compound's success in these tumors, published in Cancer Discovery, a journal of the American Association for Cancer Research.

Diffuse midline gliomas (including DIPGs with H3K27M mutations) are particularly aggressive, with an overall survival rate of only 11-15 months. These tumors are most common in children and young adults. The only treatment available is radiation therapy, but even that is difficult because the tumor is located in a brain region with critical functions.

"This is a very difficult tumor to treat," said senior author Carl Koschmann, M.D., associate professor of pediatric neurooncology and director of clinical science at Michigan Medical School's Chader-Carr Pediatric Brain Tumor Center. Prior to this study, more than 250 clinical trials had failed to improve treatment outcomes. This is a major chink in the armor."

In two clinical trials of 71 patients with diffuse midline glioma with the H3K27M mutation, patients with tumors that had not recurred at enrollment had a median overall survival of nearly 22 months, and nearly a third survived for more than two years.

ONC201's path to clinical trials has been unusual. The researchers found that the drug can cross the blood-brain barrier, which is one of the biggest challenges in designing brain tumor drugs. Initial trials in glioblastoma were not successful, but a small number of DMG patients carrying the H3K27M mutation achieved better results. Without understanding why the results were better in these patients, they began a Phase I trial in children and young adults with H3K27M mutant DMG.

In the meantime, Koschmann and co-author Sriram Venneti, MD, are trying to figure out what's going on in these tumor cells.

Through the experiment, they collected cerebrospinal fluid from the patients. They used this cerebrospinal fluid to analyze changes in metabolism and found that ONC201 entered tumor cells and affected mitochondria. Patients who responded to the drug had increased production of a metabolite called L-2HG by their tumor cells.

Koschmann called the finding "very unexpected." The team found that the increase in L-2HG reversed tumor-defining epigenetic signals, causing tumor cells to differentiate more and divide less. The longer patients took ONC201, the more the tumors showed these epigenetic reversals.

"This could explain why these patients respond so well to this drug, because they have this particular epigenetic abnormality that can be turned off by ONC201." "The tumor has an epigenetic change caused by the H3K27M mutation, and ONC201 metabolically eliminates that change," said Venneti, associate professor of pathology and pediatrics at Michigan Medical School and research director of the Chad Carr Pediatric Brain Tumor Center.

Additional clinical trials are currently underway, including testing ONC201 in combination with other therapies. Researchers at the University of Michigan's Chader-Carr Pediatric Brain Tumor Center are also continuing to study how to overcome resistance to ONC201 through combination drugs.

Koschmann noted that even nearly doubling the survival rate would not be enough for the families of patients with the disease, because the tumors are still very deadly. But he hopes this first step will lead to bigger leaps in the future.

"Now, we have a population of patients who didn't have drugs before, and now we see many tumors responding," he said. We have a platform that we can use, and we can explain why it works."

"We are very excited about this study, and ONC201 is expected to become the standard treatment for these patients in the near future," Venneti said.

Scientists discover potential drug candidates to treat brain tumors.

Clinical studies have shown that patients with diffuse midline glioma treated with ONC201 have prolonged survival; The study also explains the underlying mechanism behind the drug's success. For the first time, researchers have identified a potential drug candidate that promises to improve treatment outcomes for patients with a particular type of childhood brain tumor. The compound, known as ONC201, has been observed to nearly double the survival rate of patients diagnosed with diffuse midline glioma (DMG) or diffuse medial pontine glioma (DIPG).

University of Michigan Health Rogel Cancer Center and Chad Carr Pediatric Brain Tumor Center Center, an international team of researchers reported the findings.

In addition to reporting the results of two early-stage clinical trials, the paper reveals the underlying mechanisms underlying the compound's success in these tumors, published in Cancer Discovery, a journal of the American Association for Cancer Research.

Diffuse midline gliomas (including DIPGs with H3K27M mutations) are particularly aggressive, with an overall survival rate of only 11-15 months. These tumors are most common in children and young adults. The only treatment available is radiation therapy, but even that is difficult because the tumor is located in a brain region with critical functions.

"This is a very difficult tumor to treat," said senior author Carl Koschmann, M.D., associate professor of pediatric neurooncology and director of clinical science at Michigan Medical School's Chader-Carr Pediatric Brain Tumor Center. Prior to this study, more than 250 clinical trials had failed to improve treatment outcomes. This is a major chink in the armor."

In two clinical trials of 71 patients with diffuse midline glioma with the H3K27M mutation, patients with tumors that had not recurred at enrollment had a median overall survival of nearly 22 months, and nearly a third survived for more than two years.

ONC201's path to clinical trials has been unusual. The researchers found that the drug can cross the blood-brain barrier, which is one of the biggest challenges in designing brain tumor drugs. Initial trials in glioblastoma were not successful, but a small number of DMG patients carrying the H3K27M mutation achieved better results. Without understanding why the results were better in these patients, they began a Phase I trial in children and young adults with H3K27M mutant DMG.

In the meantime, Koschmann and co-author Sriram Venneti, MD, are trying to figure out what's going on in these tumor cells.

Through the experiment, they collected cerebrospinal fluid from the patients. They used this cerebrospinal fluid to analyze changes in metabolism and found that ONC201 entered tumor cells and affected mitochondria. Patients who responded to the drug had increased production of a metabolite called L-2HG by their tumor cells.

Koschmann called the finding "very unexpected." The team found that the increase in L-2HG reversed tumor-defining epigenetic signals, causing tumor cells to differentiate more and divide less. The longer patients took ONC201, the more the tumors showed these epigenetic reversals.

"This could explain why these patients respond so well to this drug, because they have this particular epigenetic abnormality that can be turned off by ONC201." "The tumor has an epigenetic change caused by the H3K27M mutation, and ONC201 metabolically eliminates that change," said Venneti, associate professor of pathology and pediatrics at Michigan Medical School and research director of the Chad Carr Pediatric Brain Tumor Center.

Additional clinical trials are currently underway, including testing ONC201 in combination with other therapies. Researchers at the University of Michigan's Chader-Carr Pediatric Brain Tumor Center are also continuing to study how to overcome resistance to ONC201 through combination drugs.

Koschmann noted that even nearly doubling the survival rate would not be enough for the families of patients with the disease, because the tumors are still very deadly. But he hopes this first step will lead to bigger leaps in the future.

"Now, we have a population of patients who didn't have drugs before, and now we see many tumors responding," he said. We have a platform that we can use, and we can explain why it works."

"We are very excited about this study, and ONC201 is expected to become the standard treatment for these patients in the near future," Venneti said.