Summary: A precision pediatric oncology study from the Medical University of South Carolina identifies a dual-targeting strategy to prevent relapse of medulloblastoma, the most common malignant childhood brain tumor. Although many children respond to front-line therapy, about 30% experience recurrence driven by a small, therapy-resistant population of slow-dividing, self-renewing tumor cells. The investigators show that activating the protein CK1α with an FDA-approved compound, pyrvinium, simultaneously shuts down two key survival pathways and effectively blocks the cells that fuel recurrence.
Key Facts
- The recurrence problem: Medulloblastoma is the most common malignant pediatric brain tumor. Standard treatments often reduce the primary mass, but roughly 30% of children experience relapse, and survival after recurrence is poor.
- Hidden, resistant cells: A small subset of slow-dividing, self-renewing tumor cells evades conventional therapies aimed at rapidly dividing cells. These residual cells are poised to reinitiate aggressive tumor growth.
- Dual-pathway vulnerability: The MUSC Hollings team targeted CK1α, a regulator that controls both the GLI pathway (driving active tumor growth) and the WNT pathway (supporting self-renewal). Targeting CK1α blocks both routes cancer cells use to survive.
- Pyrvinium activates CK1α: Pyrvinium, an FDA-approved compound under investigation in oncology, activates CK1α. In preclinical models it suppressed GLI-driven proliferation and eliminated WNT-dependent self-renewal, reducing tumor stemness and delaying relapse more effectively than single-pathway approaches.
- Improving brain delivery: Native pyrvinium has limited brain penetration. Researchers developed and tested a modified, brain-permeable derivative that reaches tumor tissue and shows promising preclinical activity.
- Reducing long-term harm: Precision agents that target the cells causing recurrence could lessen the developmental and long-term toxicities children face when adult chemotherapy protocols are repurposed for pediatric patients.
Source: Medical University of South Carolina
Stopping cancer from coming back is the focus of new research from MUSC Hollings Cancer Center, where scientists are targeting the cells that drive recurrence in an aggressive pediatric brain tumor.
For most children diagnosed with medulloblastoma, initial treatment yields encouraging survival rates. Yet for a significant minority—about 30%—remission is followed by a return of disease that is often more aggressive and far harder to treat.
“Once the tumor comes back, long-term survival is close to zero,” said Jezabel Rodriguez Blanco, Ph.D., who leads the study at MUSC Hollings and the Darby Children’s Research Institute. “Our goal is to stop the cells that enable relapse.”
Published in Cell Death & Disease, the study pinpoints a way to reduce relapse by attacking the small population of tumor cells most likely to survive standard treatment and later drive new growth.
Targeting the root of relapse
The research focuses on a minority population of tumor cells that can self-renew and divide slowly. These cells rely on biological pathways distinct from the bulk tumor, allowing them to survive therapies that target rapidly dividing cells and then reestablish disease.
“These cells are resistant to therapy,” Blanco said. “Because they divide less, many treatments miss them. But they’re the ones that drive recurrence.”
To address this, the team broadened their strategy beyond suppressing tumor growth alone. They sought to disrupt the signals that sustain relapse-driving cells by targeting CK1α, a master regulator that controls both:
- GLI signaling, which promotes active tumor proliferation.
- WNT signaling, which supports cellular self-renewal and stem-like behavior.
Previous work from the group had shown GLI inhibition slows growth and reduces relapse risk. In this study they tested pyrvinium, an FDA-approved drug known to increase CK1α activity and destabilize GLI. Activating CK1α with pyrvinium suppressed GLI-driven proliferation and, importantly, also blocked WNT-dependent self-renewal. That dual effect led to reduced numbers of Sox2⁺ and CD15⁺ tumor stem cells in mouse and patient-derived models, impaired tumor engraftment, extended time to relapse, and lowered relapse risk.
“Cancer cells are adept at escaping when a single pathway is blocked,” Blanco explained. “By shutting down both GLI and WNT via CK1α activation, we reduce the cancer’s escape routes.”
Encouraging preclinical results, early stage work
While results in laboratory and animal models are promising, Blanco emphasized the research is at an early stage. A major clinical challenge remains: drug delivery to the brain. Standard pyrvinium does not effectively cross the blood-brain barrier, so the team created and evaluated a brain-penetrant derivative (referred to in the study as SSTC3) that shows improved central nervous system exposure and activity in preclinical experiments.
Before clinical use in children, researchers must further refine the compound, complete safety testing, and establish optimal dosing. Because pediatric tumors and developing brains respond differently than adult patients, carefully designed studies are essential to ensure both efficacy and safety.
Beyond survival, reducing long-term treatment-related harm is a central goal. Current protocols adapted from adult cancers can cause lasting developmental deficits and increase future cancer risk. A targeted approach that eliminates relapse-driving cells could preserve both life and quality of life for survivors.
“If we can eliminate the cells at the root of relapse, we have a real chance to change outcomes for these children,” Blanco said.
Key Questions Answered:
A: Standard treatments target rapidly dividing tumor cells and typically shrink the main tumor mass, but they miss a small population of slow-dividing, self-renewing cells. Those residual cells survive treatment, rely on distinct survival pathways, and can later drive a more aggressive recurrence.
A: Pyrvinium activates CK1α, which simultaneously suppresses GLI signaling that drives proliferation and WNT signaling that supports self-renewal. By closing both pathways at once, the drug reduces the tumor’s ability to evade treatment.
A: The main obstacle is delivery to the brain. The standard form of pyrvinium does not cross the blood-brain barrier effectively. The MUSC Hollings team developed a brain-penetrant derivative and is working to optimize its safety and efficacy for children before clinical trials can begin.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal article reviewed in full.
- Additional context added by staff.
About this brain cancer research news
Author: Leslie Cantu
Source: Medical University of South Carolina
Contact: Leslie Cantu – Medical University of South Carolina
Image: Image credit: Neuroscience News
Original Research: Open access. “CK1α agonists attenuate medulloblastoma stemness and relapse risk” by Kendell Peterson et al., published in Cell Death and Disease. DOI: 10.1038/s41419-026-08762-6
Abstract
CK1α agonists attenuate medulloblastoma stemness and relapse risk
Although many children with medulloblastoma have favorable outcomes, patients in the Sonic Hedgehog (SHH) subgroup with TP53 mutations (the SHHα subtype) face higher relapse risk and poorer prognosis. The study identifies a non-canonical GLI-driven Sox2⁺ cell population that promotes relapse in SHH medulloblastoma. Pyrvinium, an FDA-approved compound that increases CK1α activity and destabilizes GLI, was evaluated alongside a brain-permeable derivative (SSTC3) in mouse and patient-derived SHHα models.
Pyrvinium suppressed GLI-driven proliferation of Sox2⁺ cells and, unlike many GLI-targeting strategies, also reduced WNT-dependent CD15⁺ self-renewing cells. Mechanistic analysis revealed that CD15⁺ self-renewal is driven by WNT signaling, which becomes de-repressed when p53/microRNA-34a control is lost. Both pyrvinium and the brain-penetrant SSTC3 reduced Sox2⁺, CD15⁺, and dual-labeled populations, impaired primary and secondary tumor engraftment, and diminished tumor stemness in preclinical models.
These results establish CK1α as a therapeutically relevant vulnerability in SHHα medulloblastoma. While pyrvinium itself may not be an ideal clinical candidate for brain tumors, the findings support development of second-generation, brain-penetrant CK1α-targeting compounds to lower relapse risk and improve outcomes for children.