Development of whole-brain in vivo 2HG imaging for precision medicine in mutant IDH glioma

7. 项目总结/文摘

7. Project Summary/Abstract There is an urgent need to improve outcomes of patients with malignant primary brain tumors. According to SEER and CBTRUS the median 5-year survival rate for CNS cancer patients improved from 32.3% to 34.4% over the last twenty years, which is among the lowest in adult malignancies and well bellow the combined survival rate of 67.2% for all cancers. This lack of improvement in patient outcomes is not explained by lack of new discoveries, but due to limited success in translating this knowledge into clinical benefit. The long-term goal of our research is translation of new in vivo molecular imaging methods in neuro-oncology to facilitate early diagnosis, guided therapy and treatment monitoring. Mutations of isocitrate dehydrogenase (IDH) in glioma offer great diagnostic and therapeutic opportunities to improve patient outcomes. IDH mutations are highly relevant for glioma because they are: 1) early driver mutations, 2) localized strictly within tumor cells, including cancer stem cells, 3) frequently present in glioma patients, 4) have better prognostic. Hence, a method that can specifically image IDH mutations in patients will have the positive impact to assess tumor burden at the initial diagnosis and during subsequent treatment follow up. In particular, determining the three dimensional extent of infiltrative tumors and aggressive cell clones is one of the most challenging problems, and in many cases explains treatment failure due to suboptimal therapy. Diagnosis and surveillance of mutant IDH glioma can be improved because of large accumulation of the metabolite 2-hydroxyglutarate (2HG) as a very specific biomarker for IDH mutations. The objective in this application is to develop whole brain quantitative 2HG imaging for diagnosis, treatment guidance and monitoring of mutant IDH glioma. The central hypothesis of our proposal is that technical improvement of in vivo 3D magnetic resonance spectroscopic imaging (MRSI) can significantly extend the clinical utility of quantitative 2HG imaging to a larger group of mutant IDH glioma patients and enable precision medicine for them. Three specific aims will be performed to achieve this goal: 1) develop whole-brain 3D MRSI for 2HG imaging of mutant IDH glioma, 2) develop absolute quantification of 2HG levels from whole-brain 3D MRSI, and 3) validate whole-brain 2HG imaging and absolute quantification in mutant IDH glioma patients. A strong rationale for the proposed research is that no alternative in vivo imaging method is specific for IDH mutations, while 2HG edited MRSI is completely non-invasive, safe, can be repeated without risks, fast and cost effective. These advantages compare well also to molecular and genetic analysis relying on biopsies with great risks and costs for glioma. The approach is innovative because it employs the first available in vivo 3D imaging method for 2HG, which will be significantly improved during this project. The contribution of the proposed research will be significant because it will provide clinicians with an effective diagnostic, planning, guiding and monitoring tool for mutant IDH glioma.