Tag: medulloblastoma

Categories : CancerTags :

New Discovery Nips Childhood Brain Tumour in the Bud

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Credit: National Cancer Institute

Scientists at The Hospital for Sick Children (SickKids) have discovered a way to stop tumour growth before it starts for a subtype of medulloblastoma, the most common childhood malignant brain cancer.

Brain cancer presents a unique set of challenges for researchers – by the time a person experiences symptoms, the tumours are often so complex that the fundamental mechanisms driving the tumour growth are no longer easy to identify. A research team led by Dr Peter Dirks is working to combat this challenge for sonic hedgehog (SHH) medulloblastoma.

In a new study published in Nature Communications, the researchers identify that a protein is responsible for awakening ‘sleeping’ stem cells and driving SHH medulloblastoma tumour formation and regrowth. By blocking this protein and preventing the stem cells from waking, the study demonstrates what could be a pivotal treatment strategy for the cancer, utilising cutting-edge genomic approaches in combination with functional experiments in a preclinical model.

“Our findings offer a novel strategy to target cancer stem cells, providing hope for more effective treatments against aggressive brain tumours,” says Dirks, Senior Scientist in the Developmental, Stem Cell & Cancer Biology program and Chief of the Division of Neurosurgery.

Cancer interception in action

The research team began by examining cellular transitions that drove the development of SHH medulloblastoma tumours. They found that early in tumour development and after conventional treatments, a protein called OLIG2 would activate ‘sleeping’ stem cells, causing them to divide and grow into a tumour.

“There is order to how the cancer initiating stem cells undergo fate changes to form tumours. We can target an early transition event and intercept the entire process – essentially stopping the cancer in its earliest form,” says first author Dr Kinjal Desai, a postdoctoral researcher in the Dirks lab.

During these transitions, the researchers uncovered a key window during which tumour progression could be blocked. By combining a previously established treatment with a small molecule called CT-179, which disrupts the OLIG2 protein, the research team were able to target the residual stem cells left after treatment and prevent them from re-awakening, effectively preventing tumour relapse.

Similarly for early-stage SHH medulloblastoma, CT-179 prevented the tumour from forming and significantly increased survival rates in the preclinical model.

Together with additional preclinical models in a study published simultaneously in Nature Communications from colleagues at Children’s Healthcare of Atlanta and QIMR Berghofer Medical Research Institute in Australia, the findings showcase what could be an effective new treatment for SHH medulloblastoma, as well as other brain cancers including diffuse intrinsic pontine glioma (DIPG).

Model of proposed role of Olig2 and OLIG2 inhibition in tumour initiation and relapse; created in BioRender.com. Desai et al., Nat. Comm. 2024.

The study complements recent research from the Dirks Lab in Nature, which describes the early stages of glioblastoma development. While future research will expand these findings into clinical trials for patients, particularly among those being monitored for relapse, the Dirks lab, part of the Arthur and Sonia Labatt Brain Tumour Research Centre (BTRC), is excited for the diagnostic potential this discovery presents.

“At SickKids, we’re already genetically testing every child with cancer to inform their diagnosis and treatments – our study goes beyond genetic testing to precision biology,” says Dirks. “I am excited for a future where this ‘magic bullet’ for early treatment could be combined with diagnostic tests to potentially prevent the cancer from developing at all.”

Source: The Hospital for Sick Children

Categories : CancerTags :

Pancreatic Cancer Drug is Promising Against Most Aggressive Medulloblastoma Subtype

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Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0

A drug that was developed to treat pancreatic cancer has now been shown to increase symptom-free survival in preclinical medulloblastoma models – all without showing signs of toxicity. Survival rates for medulloblastoma vary according to which one of the four subtypes a patient has, but the worst survival rates of about 40%, are for Group 3. The research, published in the Journal of Clinical Investigation, focused on this most aggressive subtype.

Jezabel Rodriguez Blanco, PhD, an assistant professor at Medical University of South Carolina, led the research. Her work focused on the drug triptolide, which is extracted from a vine used in traditional Chinese medicine, and its water-soluble prodrug version, Minnelide. A prodrug is an inactive medication that the body converts into an active drug through enzymatic or chemical reactions.

MYC is an oncogene, or gene that has the potential to cause cancer. MYC is dysregulated, or out of control, in about 70% of human cancers, and it shows up in much higher levels in Group 3 medulloblastoma than in the other medulloblastoma subgroups. Despite its well-known role in cancer, this oncogene historically has been considered impossible to target with drugs.

Despite its poor druggability, previous research in other cancers had shown that triptolide and its derivatives had the ability to target MYC. When Blanco was still a postdoctoral fellow at the University of Miami, her mentor, David Robbins, PhD, attended a presentation by the research team that showed that the more copies of MYC that a tumour has, the better that triptolide works.

“He came to me, and he told me, ‘You know, as Group 3 medulloblastoma has many MYC copies, you should get some research models and try the drug,” Blanco recalled. She started the project from scratch. “I started talking to people, getting cell lines and animal models, learning how to propagate them, getting the drug, using it.” 

Blanco received initially received grants to on the Group 3 research, and continued it as a side project. She knew how well triptolide was working in these hard-to-treat tumours, and she did not want her initial results to fall through the cracks.

Determining the mechanism of action has been the most challenging part of the project, she noted, due to the drug’s multiple effects, and there could still be additional mechanisms beyond those that Blanco identified.

“It was affecting MYC gene expression by affecting the RNA pol II activity, and then it was affecting how long the protein lasts. So, the fact that it’s working through two different mechanisms on this oncogene may explain why it’s so effective in tumours that have extra copies of MYC,” she said, explaining that RNA polymerase II is a protein that helps to make copies of DNA instructions, which are used to produce proteins in the cell.

Despite the challenges of narrowing down the mechanism of action specific to the cancer, it was quite clear that however it worked, it did work, she said.

The efficacy was 100 times higher in the Group 3 tumours with extra MYC copies than in the Sonic Hedgehog tumours with normal levels of MYC, she said. She found that Minnelide reduced tumour growth and the spread of cancer cells to the thin tissues that cover the brain and spinal cord, called leptomeninges. It also increased the efficacy of the chemotherapy drug cyclophosphamide, which is currently used in treatment.

Blanco decided to move forward with publication rather than waiting to write a manuscript that answered all possible questions. Knowing that most parents whose children receive a Group 3 medulloblastoma diagnosis will lose their child in less than two years was the incentive she needed to push this work out.

“There was a point at which I could not hold these data anymore because it was working so well that it needed to go out,” she said. “The preclinical models were showing such a nice efficacy that it was like, ‘OK, I cannot keep on holding this work, digging deeper into the mechanism of action because the kids that have Group 3 medulloblastoma are dying while we are doing those experiments.”

Minnelide has been tested or is currently in testing in phase I and phase II clinical trials of adults with different types of cancer, including pancreatic cancer, where it showed some efficacy.

Blanco is hopeful that, with this new research on Group 3 medulloblastoma, a clinical trial for children with this disease can be launched.

Her paper is dedicated to the memory of Insley Horn, a 9-year-old Charleston girl who succumbed to one of these aggressive brain tumours. Research, Blanco said, is the only tool we have to prevent the loss of lives like Insley’s.

Source: Medical University of South Carolina