Clinical studies reveal extended survival in diffuse midline glioma patients receiving ONC201 treatment; research also explains the underlying mechanism of the drug’s success.
For the first time, a potential drug candidate has been identified by researchers that show promise in improving outcomes for patients suffering from a specific type of childhood brain tumor that currently lacks effective treatment options. The compound, named ONC201, was observed to nearly double the survival rates for patients diagnosed with diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) when compared to prior patient outcomes.
The findings are reported by an international team of researchers led by the University of Michigan Health Rogel Cancer Center and the Chad Carr Pediatric Brain Tumor Center.
In addition to reporting on the results of two early-stage clinical trials, the paper reveals the underlying mechanisms behind the compound’s success in these tumors. The paper is published in Cancer Discovery, a journal of the American Association for Cancer Research.
“It’s an incredibly difficult tumor to treat,” said senior author Carl Koschmann, M.D., associate professor of pediatric neuro-oncology and clinical scientific director of the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine. “Prior to this study, there have been more than 250 clinical trials that have not been able to improve outcomes. This is a major crack in the armor.”
A series of brain scans show a tumor shrinking in response to ONC201. Credit: Michigan Medicine
In two clinical trials testing ONC201 in a total of 71 patients with H3K27M-mutated diffuse midline gliomas, the median overall survival was nearly 22 months for tumors that had not recurred at the time of enrollment. Almost a third of the patients lived longer than two years.
ONC201 took an unusual path to a clinical trial. Initially designed to target dopamine receptors, which are upregulated in many different tumors, researchers saw that the drug passes the blood-brain barrier, one of the biggest challenges to designing drugs for brain tumors. Initial trials in glioblastoma were not successful, but a small number of patients with DMG that carried the H3K27M mutation had more promising results. Without understanding why it worked better in these patients, a phase 1 trial was started in children and young adults with H3K27M-mutated DMG.
Meanwhile, Koschmann and co-author Sriram Venneti, M.D., Ph.D., were trying to figure out what was happening in these tumor cells
Through the trial, they collected cerebrospinal fluid from patients. They used this fluid to analyze metabolic changes and found ONC201 got into the tumor cells and affected mitochondria. Patients who responded to the drug had an increase in a metabolite called L-2HG produced by tumor cells.
Koschmann called the finding “very much unexpected.” The team found that increased L-2HG reversed tumor-defining epigenetic signals causing tumor cells to differentiate more and divide less. The longer patients were on ONC201, the more tumors exhibited these epigenetic reversals.
“This could explain why this patient population was responding so well to the drug because it had this specific epigenetic abnormality that could be turned off by ONC201. The tumors have an epigenetic change caused by the H3K27M mutation and ONC201 metabolically undoes that change,” said Venneti, associate professor of pathology and pediatrics and scientific research director of the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine.
Additional clinical trials are currently underway, including testing ONC201 in combination with other therapies. Researchers at U-M’s Chad Carr Pediatric Brain Tumor Center are also continuing to look at ways to overcome resistance to ONC201 by using drug combinations.
Koschmann notes that even a near-doubling of survival is not enough for families of patients with this diagnosis, as the tumor remains very lethal. But he hopes this first step will lead to bigger leaps in the future.
“For now we have this patient population that didn’t have a drug before, and now we see many of the tumors responding. We have a platform to build on and we can also explain why it’s working,” he said.
“We are really excited about this study and envision ONC201 becoming the standard of care for these patients in the near future,” Venneti said.
News
Paralyzed Man Feels Sensation Again With Brain Stimulation Device
Aneuroprosthetic system has allowed a man with paralysis to grasp and lift objects and feel touch again. The device helped 42-year-old Keith Thomas of Massapequa, New York, who was paralyzed from the chest down [...]
Global Cancer Cases Could Surge 67% by 2050, New Report Warns
New data reveal major geographic disparities and highlight the urgent need for global action on prevention, early detection, and equitable access to treatment. For roughly one in five people worldwide, cancer will become part [...]
A Deadly Ebola-Like Virus Is Spreading. Are We Ready?
BU virologist Nancy Sullivan says the Bundibugyo outbreak in the Democratic Republic of the Congo underscores the need for broader outbreak preparedness. The death of a nurse marked the moment health officials recognized that [...]
Why Most Animal Viruses Never Become Human Pandemics
From receptor mismatch to risky human-animal interfaces, this article explains why spillover is common but true pandemic emergence remains rare. Introduction Humans are constantly exposed to animal viruses through farming, wildlife contact, and the [...]
Stem cell organoids repair heart microvessels in coronary artery disease models
A Stanford University team has shown that vascular organoids derived from human stem cells can repair the heart’s microvessel network in pigs with ischaemic heart disease – a proof-of-concept advancement that could open new therapeutic [...]
Goodbye GP waiting rooms, hello prevention at home
Prevention is suddenly everywhere in NHS reform. The recent £340m community pharmacy deal is moving more services onto the high street. Community Diagnostic Centres are being expanded, and the Neighbourhood Health Framework sets out [...]
Ebola control is weakened by mistrust and cultural insensitivity
Effective response depends on cooperation with communities and frontline workers, writes Zaeem ul Haq The current Bundibugyo Ebola outbreak in the Democratic Republic of the Congo (DRC) and Uganda is exposing dangerous gaps in [...]
Building the Brain Requires Millions of Dangerous DNA Breaks
Scientists discovered that building a healthy brain involves an unexpected step: young neurons routinely break and rapidly repair their own DNA. As the brain develops, newly formed nerve cells must travel through tightly packed tissue [...]
One Tiny Change May Explain How Viruses Jump From Bats to Humans
Scientists found that one tiny genetic change may determine whether a bat virus stays in bats or becomes a human threat. Most infectious disease outbreaks begin when a virus or other pathogen crosses from animals into [...]
Scientists Discover 250+ Genes That Could Lead to New Ways To Prevent Melanoma
The world’s largest study of mole genetics identified hundreds of genes tied to melanoma risk, uncovering potential new drug targets and paving the way for more accurate melanoma screening and prevention. Researchers at QIMR [...]
Breakthrough Diabetes Treatment Reprograms the Immune System
An engineered stem cell therapy reversed new-onset Type 1 diabetes in mice by shifting the immune system away from attacking insulin-producing cells. For more than a century, people with Type 1 diabetes have relied [...]
Taking the world’s temperature: WHO chief spotlights global health emergencies
Taking the world’s temperature on pressing health matters, WHO Director-General Tedros Adhanom Ghebreyesus provided the latest on current global challenges - and successes when it comes to international cooperation. “The outbreaks of hantavirus, Ebola and Marburg all show [...]
Scientists Create Tiny “Mini Livers” That Could One Day Replace Liver Transplants
Engineered tissue grafts could help perform key liver functions and benefit thousands of people living with liver failure. The liver is one of the body’s hardest-working organs, carrying out hundreds of vital jobs, from [...]
NanoMedical Brain/Cloud Interface – Explorations and Implications. A new book from Frank Boehm
New book from Frank Boehm, NanoappsMedical Inc Founder: This book explores the future hypothetical possibility that the cerebral cortex of the human brain might be seamlessly, safely, and securely connected with the Cloud via [...]
Scientists Discover Surprising Way To Help the Brain Recover After Stroke
A new study suggests that strengthening the body’s natural circadian rhythms may help the brain recover after stroke, even when treatment begins days after the injury. Every year, millions of people survive a stroke, [...]
Our books now available worldwide!
Online Sellers other than Amazon, Routledge, and IOPP Indigo Global Health Care Equivalency in the Age of Nanotechnology, Nanomedicine and Artifcial Intelligence Global Health Care Equivalency In The Age Of Nanotechnology, Nanomedicine And Artificial [...]
