Despite advances in treatment in recent years, children with medulloblastoma brain tumors — particularly “group 3” tumors with high levels of the proto-oncogene MYC — tend to relapse after treatment.
To further understand why the recurrence happens, University of Colorado Cancer Center researchers Bethany Veo, PhD, and Rajeev Vibhakar, MD, PhD, used the cancer center’s genomics shared resource to examine original tumor cells and relapsed tumor cells from the same patients, looking for differences that might explain why patients become resistant to therapy.
We wanted to approach this problem more comprehensively,” Vibhakar says. “We found that we had samples in our Morgan Admas Foundation Tumor Bank that were paired between the primary tumor and a relapsed tumor from the same patient, so it made sense for us to compare those to try to identify mechanisms. By doing multi-omics analysis, we can ask multiple questions, because we can do multiple kinds of analysis with the same set of patient samples.”
One finding from the genomic analysis was that the relapsed tumor cells had a population of progenitor stem cells that seemed to be driving the therapy resistance.
“We were able to look at specific populations of cells that seem to maintain themselves or even expand in the relapse samples,” Veo says. “Are these the resistant cells that are going to repopulate the tumor? We wanted to know how their chromatin is different from the rest of the tumor that died when it was exposed to therapy.”
A closer look at the resistant cells showed that they were regulated by a gene called IDH1, which altered their genetic structure to make them more resistant to treatment.
“We found this whole new pathway, and using animal models, we were able to show that if you shut down IDH1, you can revert the cells back to being more sensitive to radiation,” Vibhakar says. “We know that these stem cells are resistant not because there's new mutations in the DNA, but because their epigenetics — the way their chromatin is packaged — is what drives the plasticity of these cells into becoming resistant.”
The next step would be to find a way to inhibit IDH1 in patients, Vibhakar says, but there are no current drugs to do so. However, since IDH1 regulates multiple enzymes, the researchers are beginning to look at how inhibiting those specific enzymes might affect therapy resistance.
“What we plan to study over the next few years is which of these enzymes are critical, and what they actually do to the cells,” Vibhakar says. “Can we reprogram these cells to become more sensitive using these drugs? If we can do it in our animal models, can we then create a clinical trial? This paper has really shifted the focus of our lab.”
Eventually, Vibhakar sees a patient taking an enzyme-inhibiting drug at the same time they are receiving radiation therapy to prevent the resistance and subsequent relapse from occurring at all.
“We have questions that are going to take us through multiple years of work to try to identify which pathways are important, which pathways prevent resistance from happening,” he says. “What happens if we combine multiple pathways together? What are the mechanisms downstream of those pathways, and how does that alter the biology? Once we get to a certain level of understanding, some of these mechanisms are going to be relevant for other pediatric brain tumors outside of medulloblastoma.”
Ultimately, of course, the goal of the research is to move the needle for patients and their families, the researchers say. Currently, 70% of group 3 medulloblastoma patients relapse, so even dropping that number to 50% is a huge win, Vibhakar says.
“I'm currently dealing with a patient who has this exact tumor. He relapsed several months ago, went on a different chemotherapy, responded, and then relapsed again,” Vibhakar says. “I'm trying to find another option, but there are no good therapies, partly because we didn't know why patients relapse. Now we have a pretty good handle on some of the reasons why they're relapsing. The next step is to see, if we understand the why, can we do something about it?”