Development of next generation 2HG and metabolic MR imaging for precision oncology of mutant IDH and wildtype glioma patients

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7. Project Summary/Abstract Gliomas are rarely curable tumors with a low survival rate of 36% at five-years that is well below the average survival rate of 67.2% across all cancers, according to SEER and CBTRUS. Malignant brain tumors cause an average of 20 years of potential life lost (YPLL) for individuals diagnosed as adults, which exceeds most common cancers. Survival and YPLL have not improved for gliomas similarly to other cancers and progress is desperately needed. The lack of improvement in patient outcomes is not due to lack of new discoveries, but due to limited success in translating this knowledge into clinical benefit. Important discoveries have been made over the last decade regarding key molecular mechanisms involved in glioma initiation and growth, which have been incorporated in the latest WHO classification. IDH mutation is the primary event in glioma initiation and has become a paradigm shift in the treatment of glioma. Neuro-oncology experts (SNO, EANO) agree that brain imaging can accelerate clinical trials of targeted therapies and mandated the development of molecular imaging for highly specific and sensitive glioma imaging. The long-term goal of our research is the development of non-invasive molecular imaging methods that can be used clinically in cancer patients. IDH mutations are frequent in glioma and produce high levels of the oncometabolite 2-hydroxyglutarate (2HG) that can be imaged as a biomarker for diagnosis, prognosis, prediction, guidance of surgery and radiation, response to chemotherapy and targeted treatments. The objective of this application is to develop fast high resolution whole brain quantitative 2HG and metabolic imaging for diagnosis, treatment guidance and monitoring of mutant IDH and wildtype glioma. The central hypothesis of our proposal is that advancing next generation 2HG and metabolic imaging will enable precision oncology and accelerate clinical translation of novel targeted therapies to improve outcomes in mutant IDH and wildtype glioma patients. Three specific aims will be performed for this: 1) develop fast high-resolution whole-brain clinically robust 2HG and metabolic imaging, 2) improve sensitivity, precision, accuracy and workflow of 2HG and metabolic imaging, and 3) clinical translation of next generation 2HG and metabolic imaging in glioma patients. There are strong rationales for the proposed research: 1) there is no alternative in vivo imaging method specific for IDH mutations, 2) 2HG imaging is completely non-invasive, can be repeated safe without any radiation, can provide results fast and cost effective, 3) provides comprehensive evaluation of the entire tumor and healthy brain without the sampling bias of biopsies, 4) it can be performed pre-surgically and in tumors that cannot be operated. The approach is innovative because it employs the first available whole brain 2HG imaging method, which will be accelerated by compressed sensing, novel shim hardware to improve data quality, and transformed in a high throughput automated tool by deep learning. The contribution of the proposed research will be significant because it will provide clinicians with a user-friendly and precise tool for diagnostic, guiding and monitoring of glioma patients.