Tuesday, December 12, 2017

By Laura Hedli

By her calculations, Michelle Monje, MD, PhD, studies a cancer that each year costs the U.S. 25,000 years of life lost. These numbers are based on average American life expectancies and the decades upon decades children with diffuse intrinsic pontine glioma (DIPG) will never experience. In the class of deadly tumors known as high-grade gliomas, DIPG affects 300-400 school-aged children annually and has no known cure.

“This is one of the ‘bread and butter’ tumors for pediatric neuro-oncology; we see it all the time. I was startled and appalled at how little we knew about this tumor and how little we had to offer,” says Dr. Monje, who began her lab in 2011 and has been extremely productive in studying DIPG as it relates to postnatal neurodevelopment.

The Child Health Research Institute (CHRI) has taken note of her work. To date, Dr. Monje has received in total $733,000 from five separate CHRI awards. The most significant of these is the Bass Endowed Faculty Scholarship of $500,000, with an annual distribution of $100,000 in unrestricted funds over five years (2014-2018). Having a certain degree of financial security, far from cultivating complacency, has incentivized Dr. Monje to greenlight riskier projects.

“It puts you in a different mindset to be a little bit more high-risk/high-reward, to go for the really impactful but possibly wrong hypothesis,” says Dr. Monje. “Unrestricted funds are so crucially important for creativity. One hundred thousand dollars of unrestricted money is worth at least twice what $100,000 of restricted [is] because it allows you to nimbly follow up new ideas.”

A relatively new idea in cancer research is that a tumor can hijack normal organ functioning to help the cancer cells proliferate. Exploring this idea as it relates to high-grade gliomas, Dr. Monje’s team made a recent surprising discovery. In September, they published a paper in Nature identifying a peculiar mechanism for glioma growth—a synaptic adhesion molecule called neuroligin-3 that is used in normal brain function and regulated by brain activity. Using a knockout mouse model where neuroligin-3 was absent, they showed that the tumors failed grow.

This work built upon the lab’s earlier research, showing that neuronal activity could promote the proliferation of normal myelin-forming glial precursor cells, and similarly the progression of gliomas. This was a fascinating finding, and it highlights entirely novel therapeutic opportunities. By testing factors released by normal brain cells that influence the behavior of childhood brain cancer cells, Dr. Monje’s team identified the role of neuroligin-3. They also recently published results in Cell showing that neural precursor cells communicate with glioma cells to colonize the lateral ventricle subventricular zone, a space where high-grade gliomas in both adults and children often spread. 

Indeed, Dr. Monje’s work is an example of how studying pediatric disease can help inform adult disease. Since high-grade gliomas are nearly impossible to resect in living patients because of the way they intertwine with the healthy brain tissue, one of the most significant operations of Dr. Monje’s lab is the management of postmortem tissue donation from families of children who have died of DIPG. It began with a patient, Dylan, whose family donated his brain to Dr. Monje’s lab upon his passing. From this extremely generous gift, Dr. Monje and her team were able to culture the tumor, grow it in the lab, and establish the world’s first tumor-cell line of DIPG in 2009. They can now study DIPG’s molecular structure and observe interactions between the neurons and tumor cells that may be conserved across all high-grade gliomas.  

This incredibly valuable resource of patient-derived DIPG cells enabled Dr. Monje’s group to screen existing anti-cancer drugs for possibly useful compounds.  In 2015, her group published findings in Nature Medicine showing that a drug called panobionstat slowed the growth of DIPG, and Dr. Monje is now leading a clinical trial of that medicine for DIPG.

If you have to write a new grant that has to go through the normal funding cycle every time you have a new idea or a new insight, nothing would ever get done. Philanthropy and unrestricted funds from departmental and institutional support, it's not just important, it's necessary for creative, innovative work.

Stanford now houses over a dozen new patient-derived cultures of DIPG, and Dr. Monje’s philosophy has been to freely share these cultures with the scientific community. (Separate funding from the McKenna Claire Foundation makes this distribution effort possible.) Tumor cultures are now at over 100 labs throughout the world, and Dr. Monje doesn’t care who has that eureka moment first. Finding a cure for high-grade gliomas is more important to her than acclaim.

The Monje lab is now studying neuroligin-3’s normal biological significance and why it’s fundamental to the proliferation of tumor cells. In the Nature paper, they also reported that an enzyme that mediates the cleavage and release of neuroligin-3 could be blocked, which may lead to therapeutic interventions. They are trying to translate these results as quickly as possible so that they can expedite an application for a clinical trial.

“Like almost anything it's not a standalone therapy but it might be particularly powerful not only in slowing the progression of the cancer, but also in combination with other therapies,” said Dr. Monje about targeting an enzyme inhibitor. “We'll [ultimately] need to remove the fuel that we think is really driving growth. Kind of like the California wildfires—that's a very good analogy for what treating this disease is like. I think that neuron-glioma interaction, at a minimum, is like those 50 mile per hour winds fanning the flames.” Dr. Monje is also a recipient of CHRI’s $50,000 SPARK award, which is allowing her to pursue another project involving a promising immunotherapy strategy for DIPG.

A number of Dr. Monje’s lab members have also received CHRI funding. Erin Gibson, PhD, joined the team in January 2012 just two months after the lab was established in November 2011. Her Postdoctoral Award of $130,000 helped fund the lab’s early seminal work linking neuronal activity with increased myelination.

Myelin, an outgrowth of glia cells, forms sheaths that encase axons and is critical for brain functioning; myelination is adaptive and especially active during the first few decades of life when it helps the brain to relay signals with greater speed. Dr. Gibson was first author on a 2014 paper in Science showing that in mice increased neuronal activity promoted increased myelination, which led to changes in neurological function.  This finding supported the idea that practice strengthens neuronal circuits and results in functional improvement. It also lay the foundation for the lab’s later work showing that the same pathway involved in neuronal activity and strengthened by experience could be co-opted by glioma cells.

The CHRI award covered Dr. Gibson’s work for two years (2012-2014). She says it “allowed us to get started on asking the questions that we wanted to ask.” After studying neuroendocrinology in her doctoral program, Dr. Gibson switched to studying glia, exploring the role they played beyond being support cells in the brain. Because she also wanted to study cancer, finding a mentor in Dr. Monje was a happy coincidence. “We both sort of became glial biologists together. Because we were new to the field in a certain respect, it allowed us to feel comfortable going into the unknown.”

Dr. Monje reflects upon the culture of grantsmanship in academic medicine, one in which she is always on the lookout for new funding opportunities to sustain the operations and boundary-pushing research of her still relatively young lab. She says that without the necessary funds, scientists may opt for the safer and easier hypothesis that will likely be proven true during experiments and result a paper that pushes the field forward but only in small increments. Overall impact and significance will be blunted without high-risk, potentially transformative science.

Ultimately, she is grateful to CHRI for allowing her to do things differently for the past 5 years.

“Science is dynamic. You have to respond to what you learn,” says Dr. Monje. “If you have to write a new grant that has to go through the normal funding cycle every time you have a new idea or a new insight, nothing would ever get done. Philanthropy and unrestricted funds from departmental and institutional support, it's not just important, it's necessary for creative, innovative work.”

Laura Hedli is a writer for the Division of Neonatal and Developmental Medicine in the Department of Pediatrics and contributes stories to the Stanford Child Health Research Institute.