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 tumour in children.
Within cancerous tumours, there are special cells, called tumour-propagating cells, that drive tumour formation and growth. Since these cells can survive standard treatments like radiation and chemotherapy, the tumour 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 tumour growth.
"Tumour-propagating cells are the main reason tumours grow and come back. By targeting a specific potassium channel, we were able to reduce tumour growth without impacting surrounding healthy cells," says Dr. Xi Huang , one of the lead authors and Senior Scientist in the Developmental, Stem Cell & Cancer Biology program . "This discovery opens the door to developing new therapies that could transform how we treat this common childhood brain cancer."
Narrowing down tumour growth genes
Using a genetically engineered preclinical model, researchers in Dr. Michael Taylor 's lab uncovered a list of genes linked to tumour 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 tumour) 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 tumour 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 tumour-propagating cells multiply to drive medulloblastoma growth.
"Without KCNB2, the tumour cells began to lose their integrity, triggering a chain of events that eventually interrupts the tumour propagation process and stops tumour growth," explains Fan.
How does potassium affect tumour 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 tumour cells to swell with water, just like an overfilled balloon. As the cells expanded, their inner structures broke apart, stopping the mechanisms that cause tumours 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. For more details on funders, please read the paper in Developmental Cell .
