Researchers find that inhibiting the KCNB2 gene can reduce tumor growth, offering hope for innovative treatments for childhood brain cancer.
A team from The Hospital for Sick Children (SickKids) has discovered an important gene that may lead to advanced treatments for medulloblastoma, which is the most common type of malignant brain tumor in children.
In cancerous tumors, there exist specific cells known as tumor-propagating cells that contribute to tumor development and growth. These cells can withstand standard treatments like radiation and chemotherapy, leading to the possibility that the tumor could recur.
Recent research published in Developmental Cell suggests that targeting the KCNB2 gene may improve existing cancer therapies by addressing medulloblastoma growth.
“Tumor-propagating cells are primarily responsible for the growth and recurrence of tumors. By aiming at a particular potassium channel, we managed to decrease tumor growth while leaving healthy surrounding cells unaffected,” states Dr. Xi Huang, one of the lead authors and Senior Scientist in the Developmental, Stem Cell & Cancer Biology program. “This finding opens up avenues for creating new therapies that could change the way we treat this prevalent childhood brain cancer.”
Identifying genes linked to tumor growth
Utilizing a specially designed preclinical model, researchers from Dr. Michael Taylor’s lab pinpointed several genes associated with tumor growth. Among these, two were related to potassium channels, which facilitate the exit of potassium from cells. At the same time, an analysis of the medulloblastoma transcriptome—encompassing all the genes expressed by the tumor—indicated that potassium channels were more abundant in humans than expected.
“To find optimal therapy targets, we created a new in vivo screening method to identify genes crucial for tumor survival,” Dr. Taylor explains, who is also an Adjunct Scientist at SickKids and a Professor at Baylor College of Medicine and Texas Children’s Cancer Center in Texas. “Our approach pinpointed which essential components are necessary for sustaining the tumor, which is vital for us in our effort to eliminate medulloblastoma.”
Dr. Jerry Fan, the first author and a former Ph.D. student in Huang’s lab, investigated the genes further and discovered that one of these channels is key to allowing tumor-propagating cells to proliferate, thus fueling medulloblastoma growth.
“When KCNB2 was blocked, the tumor cells began to deteriorate, initiating a sequence of events that disrupted tumor propagation and halted growth,” Fan elaborates.
What role does potassium play in tumor growth?
Potassium is a vital ion necessary for numerous bodily functions, including maintaining normal fluid levels in our cells. Visualize it as a water balloon—if it fills up too much, it bursts. Researchers found that blocking KCNB2 made medulloblastoma cells absorb excess water, similar to an overinflated balloon. As these cells swelled, their internal structures began to break down, interrupting the processes responsible for tumor growth.
Progressing towards a new treatment for medulloblastoma
The researchers are optimistic about the potential this discovery holds for creating treatments aimed at the KCNB2 gene. With backing from the SickKids Industry Partnerships & Commercialization (IP&C) office, Huang collaborated with a specialized drug discovery firm focusing on ion channels to assess the effectiveness of over 30,000 small molecules designed to inhibit KCNB2 function.
Currently, Huang and his team are validating the prioritized molecules with plans to advance the most promising candidates into preclinical testing to determine their effectiveness.
“Finding the molecule that can optimally block KCNB2 is our next goal in developing a targeted therapy for medulloblastoma,” Huang remarks. “I appreciate the committed support from IP&C at SickKids to help ensure that these findings progress from the laboratory into tangible therapies for patients.”
This study received funding from various organizations including the Sontag Foundation, the Ontario Early Researcher Award program, the Canadian Cancer Society, and several other institutions. Michael Taylor holds a CPRIT Scholar position in Cancer Research at Texas Children’s Cancer and Hematology Center. For a detailed list of funders, please refer to the paper in Developmental Cell.
