1. Nalley, Catlin

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New research, which shows that a specific protein regulates both the initiation of cancer spreading and the self-renewal of cancer cells in medulloblastoma, could lead to a promising therapeutic approach for pediatric brain cancer (Nat Comm 2018; doi:10.1038/s41467-018-06564-9).

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"When medulloblastoma spreads, it's much harder to treat and, in many cases, virtually impossible to cure," noted Samuel Cheshier, MD, PhD, researcher at Huntsman Cancer Institute and Associate Professor of Neurosurgery at the University of Utah. "It is important to better understand this disease and how it metastasizes in order to treat the cancer and discover how to hinder its spread."


The study, which was led by Cheshier, was conducted in collaboration with Suzana Kahn, PhD, and Irving Weissman, MD, from Stanford University School of Medicine, and Sidharthra Mitra, PhD, at the University of Colorado School of Medicine, who was a co-senior author.


Study Details

In an effort to learn more about the metastasis of medulloblastoma, the research team gathered samples from patients that included a brain tumor sample and a spinal metastasis. With a focus on studying different cancer cell markers, the investigators found that NOTCH1 plays an important role in the spread of this common pediatric brain cancer.


"The methodology was twofold," Cheshier explained. One aspect of the study took a closer look at how the samples grow in culture. "We looked at how the cells self-renew, as well as how the cells grow and spread in the culture dish."


In this environment, researchers found that the NOTCH1-positive cells were always able to self-renew. Additionally, they were able to make colonies with fewer numbers of cells compared to the NOTCH1-negative cells, according to Cheshier. "We also determined that the NOTCH1-positive cells moved further distances in the dish more than the NOTCH1-negative cells," he explained.


In addition to the analysis of the cultured cells, the researchers also utilized mouse models to research the NOTCH1 pathway. To determine the metastatic potential of NOTCH1-positive cells in vivo, researchers "sorted the NOTCH1-positive and NOTCH1-negative human medulloblastoma cells from primary cerebellar xenografts."


The study authors reported that, "Although NOTCH1-positive and NOTCH1-negative cells generated similar sizes of primary cerebellar tumors, NOTCH1-positive cells produced robust spinal metastases, whereas NOTCH1-negative cells were unable to produce detectable spinal metastases and were unable to produce secondary brain tumors."


Cheshier and his team tested a monoclonal antibody that specifically targets the NOTCH1 pathway and found that "medulloblastoma-bearing mice intrathecally treated with anti-NRR1 present lower frequency of spinal metastasis and higher survival rate."


"NOTCH1 has a unique attribute that makes the cancerous cells more likely to spread and form new tumors, as well as self-renew. Understanding this interaction from signals outside the cells is a major step," noted Cheshier.


Implications, Next Steps

Findings from this study have important implications for future research and the development of a potential therapeutic approach for this difficult-to-treat disease.


"We now have another treatment target for these patients that can be delivered directly to the brain space, which will be more effective and result in fewer side effects," noted Cheshier. "Scientifically, [these findings] allow us to explore the mechanisms that drive self-renewal and metastasis, giving us a pathway to find and develop additional targets."


What is next for the research team? They are now working on building a clinical trial for medulloblastoma using the same treatment tested in the lab, which they hope will lead to a more effective therapeutic approach for this patient population.


"Scientists working in pediatric cancer have been leading the generation of molecular analysis with next-generation sequencing technologies, high-throughput bioinformatics, and artificial intelligence," said Cheshier. "A lot of science has been established and utilized in this space, which has helped to raise awareness for this patient population.


"The scientific outlook is positive for pediatric brain cancer. An increased utilization of immunotherapy and molecular approaches is changing the way we treat people and [these therapies] are being used more in pediatric patients.


"The future is smarter therapies, like targeting NOTCH1, that are more effective with less side effects," he concluded.


Catlin Nalley is associate editor.


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