Pediatric neuro-oncologist Rishi Lulla, MD, MS, and pediatric neurosurgeon Amanda Saratsis, MD, are always saddened when they must share a diagnosis of a high-grade glioma with a family since they cannot offer meaningful hope of survival to children and teenagers with this condition. High-grade gliomas are among the most aggressive cancers that originate in the brain, with the lowest survival rate among tumors.
But now there is renewed hope, as researchers and physician-scientists at the Stanley Manne Children’s Research Institute of Lurie Children’s and experts from Northwestern University Feinberg School of Medicine are developing new strategies to control these tumors through advanced technologies and epigenetics for patients and families desperate for better treatments.
Drs. Lulla and Saratsis, both assistant professors at the Feinberg School, are part of a new interdisciplinary team of physicians and researchers accelerating research to understand why these tumors form and to create effective therapies.
Tumor tissue samples are key to progress in treating high-grade gliomas. In the past, obtaining biopsies of brainstem tumors was risky for patients and did not change the outcome of their deadly disease, regardless of the pathology results.
However, safer surgical procedures for obtaining tumor tissue and new discoveries from the tissue that inform potential new therapies have been game-changing. These advances launched research into tumor epigenetics, the study of how factors outside the DNA code can cause genes to be switched on or off and affect tumor formation and response to therapy. Improvements in radiographic and MRI imaging allow Dr. Saratsis and her neurosurgical colleagues to perform pinpoint biopsies of tumors, so valuable information can be extracted from tissue samples. Surgical techniques and advanced neuroimaging technology combine to work almost like a highly intelligent GPS system within the brain, making precise biopsies possible with little risk to patients.
“It is so scary to have a needle inserted in your child’s brainstem, so I am amazed by the patients and families who are willing to allow us to obtain tissue samples in order to study their tumor biology. This will help us find more effective treatments and potentially help other children through our research,” says Dr. Saratsis.
Investigators at the Manne Research Institute and the Feinberg School are studying high-grade gliomas on the molecular level to discover precisely why they grow and do not respond to conventional brain tumor treatments. The team is driven to find differences between individual tumors by examining their unique biology.
This effort marks a landmark partnership between Lurie Children’s and outstanding basic scientists at the Feinberg School. Six investigators are collaborating to discover improved therapies that may lead to better outcomes for children and teens with malignant gliomas, including longer life expectancies and extended preservation of sensory and cognitive abilities.
Drs. Saratsis and Lulla are joined by an international leader in epigenetics research, Ali Shilatifard, PhD, Chair of Northwestern’s new Department ofBiochemistry and Molecular Genetics; C. David James, PhD, Vice Chair of Research and Professor of Neurological Surgery and Biochemistry and Molecular Genetics; Rintaro Hashizume, MD, PhD, Assistant Professor of Neurological Surgery and Biochemistry and Molecular Genetics; and Alexander Stegh, PhD, Assistant Professor of Neurology.
Connecting complementary areas of clinical and translational research expertise, these six experts are examining the process of gene expression in brain tumors and the proteins, enzymes and intercellular signaling pathways that allow unchecked cell proliferation that leads to tumor formation.
Drs. Lulla and Saratsis’s team is already working to secure NIH funding for the group’s research, and to partner with other institutions to initiate clinical trials and study more tumor samples. To qualify for this government funding, the team is building their case with data gathered through their ongoing research, currently supported by philanthropy.
Tumor epigenetics has become a central focus of the group’s research. Part of the team’s investigation is devoted to understanding how specific mutations in the genetic code affect how DNA is expressed.
Their specific area of focus is the mutation of genes encoding a specific protein that controls gene expression, Histone H3. “We now know that the Histone H3 mutation occurs in the majority of pediatric high-grade gliomas, and may be responsible for tumor development. If we can figure out how the mutation affects glioma cell biology, we can figure out how to reverse its effects,” says Dr. Lulla.
One thing is already apparent: treatment strategies for kids need to be different from adult therapies. In addition to using nanotechnology to detect and treat gliomas, these investigators are working to create new anti-cancer compounds and therapies to control gliomas while minimizing the effect on kids’ developing central nervous systems.
To delve down deep into molecular mechanisms responsible for malignant glioma formation, sophisticated, labor-intensive analysis of DNA and RNA sequences is performed on each brain tissue sample. The analysis produces enormous amounts of data that must be mined to help pinpoint molecular targets where drug compounds may be able to slow tumor progression.
Speed is paramount: most children do not live more than two years after being diagnosed with high-grade gliomas. “Right now, I am analyzing only five tumor cell lines because we have limited funds. But we have the capability to create and study cell lines from each and every patient we treat,” Dr. Saratsis says. “We want to create a library of tumor genetic profiles to thoroughly understand the process of tumor formation and match each patient with the very best therapies for their individual tumor.”
Lurie Children’s researchers are also considering novel surgical methods to place anti-cancer drugs as close as possible to tumors. Dr. Saratsis is exploring catheter-based delivery of compounds directly into tumors, while members of the research team are studying nanoparticles and intranasal drug delivery for rapid, targeted absorption of compounds into the central nervous system.
Finding better treatments for children with high-grade gliomas will involve successes and failures, but researchers are encouraged by the participation of patients and their families, advanced clinical and research technologies, and their team members whose unique expertise holds part of the answer to arresting these complex malignancies. Investigators are also hoping their research may reveal clues leading to improved treatments for other types of brain cancers.
"We are no longer at a standstill, and we have got to keep this research moving,” Dr. Lulla says.
This article was originally published in the Spring 2016 issue of Heroes magazine.