Breakthrough gene discovery offers new hope for medulloblastoma therapy

Scientists at The Hospital for Sick Children (SickKids) have identified a key gene that could lead to next-generation treatments for medulloblastoma, the most common malignant brain tumor in children.

Within cancerous tumors, there are special cells, called tumor-propagating cells, that drive tumor formation and growth. Since these cells can survive standard treatments like radiation and chemotherapy, the tumor can potentially grow back and cause a relapse. 

New research published in Developmental Cell provides evidence that targeting the KCNB2 gene could enhance current cancer treatments, tackling medulloblastoma tumor growth. 

Tumor-propagating cells are the main reason tumors grow and come back. By targeting a specific potassium channel, we were able to reduce tumor growth without impacting surrounding healthy cells. This discovery opens the door to developing new therapies that could transform how we treat this common childhood brain cancer.”

Dr. Xi Huang, one of the lead authors and Senior Scientist in the Developmental, Stem Cell & Cancer Biology program 

Narrowing down tumor growth genes 

Using a genetically engineered preclinical model, researchers in Dr. Michael Taylor’s lab uncovered a list of genes linked to tumor growth. Two of these genes were involved in potassium channels, which are pathways that allow potassium to flow out of cells. Simultaneously, an analysis of the medulloblastoma transcriptome (all the genes expressed by the tumor) show that potassium channels were present in humans above expected levels. 

“To identify ideal therapy targets, we developed a novel in vivo screening method that shows which genes are essential to tumor survival,” says Taylor, Adjunct Scientist at SickKids and Professor at Baylor College of Medicine and Texas Children’s Cancer Center in Texas. “Our method highlighted which key blocks in a tower are necessary to keep the tower standing, which is crucial for us in trying to topple medulloblastoma.” 

First author Dr. Jerry Fan, a former Ph.D. student in Huang’s lab, took a closer look at the genes and found that one of these channels plays a crucial role in helping tumor-propagating cells multiply to drive medulloblastoma growth. 

“Without KCNB2, the tumor cells began to lose their integrity, triggering a chain of events that eventually interrupts the tumor propagation process and stops tumor growth,” explains Fan. 

How does potassium affect tumor growth? 

Potassium is an essential ion which supports many human functions, including maintaining normal fluid levels within our cells. Imagine a water balloon – if it takes in too much water, it bursts. Scientists found blocking KCNB2 caused medulloblastoma tumor cells to swell with water, just like an overfilled balloon. As the cells expanded, their inner structures broke apart, stopping the mechanisms that cause tumors to grow. 

Towards a new therapy for medulloblastoma 

The researchers are excited about the possibilities this discovery offers for developing medulloblastoma treatments that target the KCNB2 gene. With support from the SickKids Industry Partnerships & Commercialization (IP&C) office, Huang worked with a specialized ion channel drug discovery company to evaluate the efficacy of over 30,000 small molecules that could inhibit KCNB2 function. 

Now, Huang and his team are validating the ranked molecules and will move the strongest candidates to preclinical models to test their efficacy. 

“Identifying the molecule that can most effectively block KCNB2 is our next milestone to develop an effective targeted therapy for medulloblastoma,” says Huang. “I am grateful to have dedicated support from IP&C at SickKids to help ensure these findings will move beyond the lab, and towards real-world therapies for patients.” 

This study was funded by the Sontag Foundation, Ontario Early Researcher Award program, Canadian Cancer Society, Cancer Research Society, Natural Sciences and Engineering Research Council (NSERC), American Brain Tumor Association, Ontario Institute for Cancer Research, Canadian Institutes of Health Research (CIHR), National Institutes of Health (NIH), b.r.a.i.n.child, Meagan’s HUG, Cancer Prevention and Research Institute of Texas (CPRIT). Michael Taylor is a CPRIT Scholar in Cancer Research and Texas Children’s Cancer and Hematology Center.