“Time is short,” says Dr. Suzanne Baker. “The survival time is so very short for these children. So the time frame for developing new therapies is in desperate need of acceleration.”
Dr. Baker was speaking about one the most devastating pediatric cancers: pediatric high-grade gliomas. Pediatric high-grade glioma patients face prognoses measured most often in months, not years. Less than 30% of these patients, on average, will survive five-years beyond their diagnosis. For diffuse intrinsic pontine glioma (DIPG) patients, the five-year survival rate is between zero and one percent.
Most die within nine months.
This group of tumors is a major reason why just last September we learned that pediatric brain tumors surpassed leukemia as the leading cause of cancer-related death in all children in America.
Coincidentally, Dr. Baker actually made the previous remarks just a few days prior to the announcement from the U.S. Centers for Disease Control and Prevention (CDC) that pediatric brain tumors had surpassed leukemia as the leading cause of cancer deaths in kids. She was participating in the September 2016 launch of the National Brain Tumor Society’s “Project Impact: A Campaign to Defeat Pediatric Brain Tumors,” an effort to raise the resources needed to fund the Defeat Pediatric Brain Tumors Research Collaborative, a program of NBTS and partners from other childhood cancer charities.
Dr. Baker is a leading researcher within the Collaborative and will be developing new laboratory models that will be used to study pediatric high-grade gliomas, and particularly how they respond to various potential new medicines.
“We need to develop model systems that really use all of the information that we have about the molecular underpinnings of the disease to help predict how pediatric high-grade gliomas cells would respond to therapies,” says Dr. Baker. “We need good models to screen clinical candidates and do preclinical testing of drugs that are currently approved for use in patients and also new drugs and chemicals that are being developed as potential future drugs…This disease, fortunately, is not very common in the general population, but that means it’s difficult to do clinical trials on a lot of different new drugs at one time. So it’s very important that we have model systems that allow us to screen through a large number of opportunities and select the ones that have the best chance of working so that those go directly into the relatively small patient population where we hope we can make an impact quickly.”
What is allowing Dr. Baker and her colleagues to begin creating better models of pediatric high-grade glioma are advances in areas such as stem cell technology, techniques for “grafting” human tumor cells into mice, more tissue available because of better surgical biopsies, and other discoveries that are informing the research field about the molecular mechanisms that make these tumors tick.
“All this information, tissue, and data lead to new mouse models,” says Dr. Baker. “There is so much variation in human pediatric high-grade gliomas, that we need multiple models to represent the whole spectrum of pediatric high-grade glioma disease biology.”
Beyond just enabling better model creation, Dr. Baker notes that recent discoveries made about these tumors in general – many by herself and other members of the Defeat Pediatric Brain Tumor Research Collaborative – have advanced the field to its most exciting point in decades.
“This is actually a very promising and exciting era for pediatric high-grade glioma research,” says Dr. Baker. “The opportunity to look across the entire genome and identify mutations in pediatric high-grade gliomas led us to some unexpected, surprising findings…The ability to sequence across the entire genome has allowed us, suddenly, to have a very big-picture look at a disease that was very understudied previously.”
The “unexpected finding” was the recent identification of mutations to a type of protein in cells called a histone. Specifically, researchers have zeroed in on mutations to a particular histone known as “H3,” that is important for how DNA is packaged into a cell’s nucleus and controlling which genes are switched on or off in a cell. Importantly, mutations to H3 are found in approximately 80% of DIPGs, but not healthy cells.
“Finding a single mutation that accounts for 80% of this disease suddenly presented an all-new, unifying mechanism that drives this disease. That made us think that maybe there would a useful way to target this therapeutically,” says Dr. Baker. “Suddenly, we have not only a very high frequency target, but a completely new method of cancer subverting normal processes and taking a normal cell and turning it into a very aggressive cancer cell. So now this opens up a lot of new opportunities on multiple levels. We’re especially interested in unique sensitivities to certain drugs.”
Now, Dr. Baker and the rest of the Defeat Pediatric Brain Tumors Research Collaborative are getting to work on studies that will help understand how these alterations ultimately disrupt the fine-tuned machinery of the cells and cause them to grow and spread uncontrollably; create the new and better models and test potential new drugs in them; and study how the mutations change or adapt in the face of treatment and/or as the tumors continue to grow.
“We all normally work independently, but we have to collaborate and get together. We need all components of this project to make things happen: discovery to understand mechanisms of mutations; biomarkers to identify potential responders; and drug screening to find active agents.”
Ultimately, Dr. Baker says she hopes that the Collaborative can make the necessary progress to inform new treatment strategies that lead to more rational clinical trials and approaches to tailoring therapies for patients that will yield increases in overall survival and quality of life achievements.
“We need to keep the momentum up from finding mutations, to understanding how they work, to understanding how that impacts clinical decisions,” says Dr. Baker. “There are a number of outstanding groups in this project. We need to work together. We can move more quickly if we work together and accelerate progress. If we can truly understand how the disease actually develops, we can build better therapies.”
Dr. Baker notes what a special opportunity participating in the Collaborative presents for herself, her colleagues, the entire field, and, most importantly, patients and their families.
Dr. Suzanne Baker is Director, Brain Tumor Research Division; Co-Leader, Neurobiology & Brain Tumor Program; and Endowed Chair in Brain Tumor Research at St. Jude Children’s Research Hospital. She is a leader in the field of pediatric neuro-oncology, and a lead investigator in the National Brain Tumor Society’s Defeat Pediatric Brain Tumors Research Collaborative, where she will focus on creating better models to study pediatric high-grade gliomas and well as screening to identify potentially effective drugs.
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