Using Single-Cell Approaches to Determine the Mode of Disease Progression in IDH-Mutant Non-Codeleted Glioma
Abstract
The fiscal year 2018 Peer Reviewed Cancer Research Program Topic Area is brain cancer. Adult patients suffering from a glioma are clinically divided into three groups based on molecular markers present or absent in their tumors. The subset of glioma characterized by a specific mutation and also exhibiting a specific DNA signature represents approximately 30% of the adult glioma patient population and has a median survival of 75 months. Patients are typically diagnosed in their late thirties resulting in an excessive number of life years lost. There is thus an urgent need for better understanding of the biology of this particular type of glioma to stimulate the development of new ways of treatment. Our specific type of DNA profiling studies have shown that this specific type of glioma can be further subdivided into two groups, each with a further, specific type of DNA signature: one signature termed G-CIMP-high has a relatively favorable outcome, while the other, termed G CIMP-low, consists of patients at risk of early disease progression. Additional work has suggested that the G-CIMP-low signature is found in up to 50% of recurrent gliomas and represents a more malignant disease state. Understanding the origin of the G-CIMP-low signature provides a basis for the design of rational therapies. However, while many cancer types can be modeled in petri dishes or using laboratory mice, it has proven particularly challenging to grow cells taken from gliomas outside their natural environment. Our inability to establish appropriate model systems has severely hampered progress in clinical treatment of this disease. The scientific objective of this proposal is to determine the pattern of tumor evolution and recurrence in a specific, aggressive type of glioma using novel, state-of-the-art technology. The rationale for the proposed study is that there is a paucity of disease models for glioma impeding our understanding of glioma evolution and recurrence, and preventing the development of biomarkers to track the progress of the disease and the expansion of options to treat this devastating disease. Recent technological developments have enabled us to study DNA patterns in single glioma cells. Such approaches need to be exploited for detailed studies of patient tumor samples, in particular because of the paucity of disease models. Here, we will use sophisticated single-cell DNA characterization approaches with the following goals: (1) to determine the frequency of G CIMP-low cells in primary glioma tumors, and (2) to compare the DNA characteristics of primary gliomas to their matching tumor after disease recurrence. These studies will identify the populations of cells that are the root for the disease recurrence, and will help to characterize the progression of this type of glioma. These cells are resistant to the toxic challenges of chemo- and radio-therapy, thereby driving glioma relapse, and the knowledge that will be derived from this project will provide a basis toward developing new treatments to target these cells. The outcome of this research is anticipated to be that we will define the DNA signatures that underlie brain cancer progression and recurrence. The impact of this research is that it will provide novel molecular insights to specific subtypes of glioma, enabling the development of specific biomarkers and establishing a foundation for personalized treatment plans. The military relevance Focus Area is: Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries. With a median diagnosis age of 38, IDH-mutant non-codel glioma is expected to significantly impact active duty Service members and Veterans across all branches of the military based on recent US military age demographics, with nearly 18% of ac
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910246
Entities
People
- Roeland Verhaak
Organizations
- Jackson Laboratory
- United States Army