Targeting GABAergic Neuronal Signaling to Suppress IDH-Mutant Glioma Proliferation
Abstract
Career Goals in Cancer Research: The research career goal of the Principal Investigator (PI), Dr. Lee, is to investigate the biology of brain tumors, with a particular focus on interactions between tumors and their neuronal microenvironment, in order to improve treatments for patients with these fatal cancers. The Horizon Award will provide critical opportunities for Dr. Lee to advance her career as an independent researcher at the forefront of brain cancer research, by enabling her to acquire advanced training in cancer biology to complement her expertise in neurophysiology and developmental genetics. Results from this project will lay the groundwork for a range of important questions on the interactions of brain tumors with neuronal and glial parenchyma, which Dr. Lee is committed to continuing to study in the future. Scientific Objective and Rationale: One of the most significant recent discoveries in glioma biology has been the identification of mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 in a large subset of gliomas. IDH-mutant gliomas are unique in that they afflict younger adults, ages 20 to 45 years old, and are often classified as low-grade gliomas at the time of diagnosis. Despite maximal surgical resection and medical treatments, these initially slow-growing tumors unfortunately usually recur in highly malignant and invariably fatal form. One of the main pathways to making an impact on brain cancer research is the development of effective treatment approaches, as currently there are no definitive cures for these cancers. One aspect of brain tumors which has been understudied is how glioma cells interact with the normal cells in the brain, such as neurons and glia, and what effects the normal cells may have on tumor growth. Some reports have suggested that neuronal activity can promote tumor growth, while others have reported suggested that neurons normally prevent uncontrolled tumor growth and promote differentiation of cells. The tumor cells may express a type of surface receptor called GABAA receptors (GABAARs), which normally restrict stem cell and progenitor proliferation. Our hypothesis is that inhibitory neurons, many of which release GABA, normally serve to control the growth of glioma cells in early stages of tumor development. Later, the glioma cells are able to escape the suppression of the neurons by secreting a metabolite, D-2-hydroxyglutarate, which may be toxic to neurons and thus prevent the neurons from suppressing tumor growth. We aim to study this hypothesis using tools to record the electrical signals of the tumor cells directly and to observe whether tumor growth changes as these receptors are manipulated. Applicability of the Research: Results of this research will provide new insight into the drivers of IDH-mutant gliomas progression and the understudied realm of glioma-neuron cross-talk, as well as improving our understanding of tumor-associated seizures. This information will be able to help patients with IDH-mutant tumors by allowing us to understand whether activating GABAA receptors with certain medications may prevent the growth of tumors in these patients. Our research may also help patients with tumor-associated seizures or other types of epilepsy. This is due to the fact that we will be recording from neurons around the tumor cells, which may give us new information about how seizures, which are increased in patients with brain tumors, arise in these patients or patients with other diseases, and may be able to be controlled with certain medications more effectively and with fewer side effects. The time it may take to achieve a clinically achievable outcome will likely be on the order of years, with regards to suppressing tumor growth, but the time to achieve outcomes regarding the improved control of seizures in tumor patients will be substantially shorter, likely on the scale of weeks to months. Contributions: IDH-mutant gliomas typically afflict young
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910731
Entities
People
- Christine K Lee
Organizations
- Massachusetts General Hospital
- United States Army