One Year Research Update:
Eric Raabe, MD, PhD at Johns Hopkins University is a CureSearch Young Investigator studying the effect of a genetic mutation on the development of diffuse intrinsic pontine glioma (DIPG), a rare and difficult-to-treat brain tumor affecting children. Dr. Raabe studies the H3F3A mutation, which is present in about 80% of cases of DIPG. By studying this mutation, Dr. Raabe hopes to better understand how DIPG tumors are formed and how they grow.
In his first year of research as a CureSearch Young Investigator, Dr. Raabe studied cell culture models of DIPG in order to understand how the cancer originates and grows. Cell culture models are important because they allow scientists to model the behavior of disease in a laboratory. In Dr. Raabe’s work, he used models of DIPG cells to study its genetic structure and growth and to identify its genetic program. DIPG cancerous cells have a genetic change that inhibits the “off-switch” that tells a cell to stop replicating. In normal cells, this “off-switch” prevents a cell from replicating more than necessary. In DIPG, the “off-switch” is silenced, which causes the cancer to grow. CureSearch funding enabled Dr. Raabe to make progress in understanding the “epigenetic landscape” of DIPG, meaning that he better understands why these cells mutate in the first place and how they continue to grow. Dr. Raabe has discovered that in DIPG cells, a particular enzyme called TET is over-active. This enzyme contributes to silencing the “off-switch.” By targeting this enzyme, researchers might be able to ensure that the “off-switch” functions properly, inhibiting the growth of DIPG. The results of this study were published this summer in Acta Neuropathologica Communications, and Dr. Raabe and his team presented their findings at several major conferences this year.
In his second year of research, Dr. Raabe will test techniques that target enzymes in DIPG that contribute to its growth. He will also test drugs that target DIPG’s disrupted “off-switches” and inhibit the growth of the cancer. If Dr. Raabe and his team can discover key pathways that lead to cellular regulation in DIPG, this may allow researchers to develop drugs that target these pathways.
Diffuse Intrinsic Pontine Glioma (DIPG) is one of the most devastating childhood cancers, with mean survival times of a little more than a year. DIPG is a type of central nervous system cancer that is located in the pons section of the brain. The pons controls breathing and swallowing, as well as movement in the face and head, and arms and legs. DIPG tumors cannot be removed because they lack an identifiable border, and they take over a location in the brain necessary for survival.
DIPG is a very rare childhood cancer and primarily affects children between 3-10 years old. The cancer is treated aggressively with radiation but in the last 30 years, no other treatments have been shown to extend a child’s life beyond 1 to 2 years. Diagnosed by unique characteristics that appear on MRI, until recently there was very little DIPG tissue available for researchers to study. Thanks to new autopsy processes, in recent years researchers have begun to study DIPG tissue and in doing so have found that a specific gene mutation is present in about 70% of DIPG tumors.
Eric Raabe, MD, PhD assistant professor of pediatric oncology at Johns Hopkins University, hypothesizes that this mutation is necessary for the initial formation of the tumor but is not necessary for its continued growth. He wants to understand how this founder mutation leads normal neural stem cells (the cells that develop into the body’s nervous system) to develop abnormally, how this abnormal growth then leads to the formation of a DIPG tumor, and what role, if any, the initial mutation plays in the continued growth of the tumor.
To conduct his research, Dr. Raabe will first place the mutation into healthy neural stem cells in the laboratory and watch them to see how this mutation affects the other genes in the cell. He will also determine if having this mutant gene alters the cells’ ability to grow into more mature cells. Then, Dr. Raabe will take these mutant cells and place them into mice. The mice will be watched as they develop DIPG to determine how the core mutation changes how the tumor forms, and continues to grow.
Dr. Raabe hopes that his research will lead to an understanding of what causes DIPG to form, and what allows DIPG to continue growing. If these are known, researchers could begin testing medications against the mutations in the laboratory to see what might prove effective in patients.
Dr. Raabe is funded by CureSearch for two years and during this time, we look forward to sharing progress of his work.