Research Project
8981399
? DESCRIPTION (provided by applicant): Glioblastoma accounts for ~17% of all brain tumors and is the most common and most malignant form of glioma. Primary glioblastomas show rapid disease progression without precursor lesions, whereas secondary glioblastomas generally originate as low-grade astrocytomas that form grade IV gliomas over a period of 5-10 years. Without prior knowledge of a patient's tumor progression, diagnosing primary vs. secondary glioblastoma is difficult because the diseases cannot be readily distinguished by histopathology. Point mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are observed in up to 80% of grade II and III oligodendrogliomas, astrocytomas, and secondary glioblastomas, but only occur in <7% of primary glioblastomas. Several IDH1 and IDH2 point mutations can promote the conversion of the normal metabolic product (a-ketoglutarate) to the oncometabolite D-2-hydroxyglutarate. IDH1 or IDH2 mutations in glioma patients are predictive of improved overall survival and progression-free survival, compared to glioma patients with wild-type (WT) IDH1 and IDH2. Patients with mutant IDH1 may also have increased overall survival rates when treated with VEGFR-targeted therapy following recurrence, when compared to EGFR-targeted therapy. Promising targeted therapeutics against mutant IDH1 and IDH2 are currently being investigated in clinical trials. Thus, knowing a patient's IDH1 and IDH2 mutational status can impact treatment decisions for first and second-line therapy. GeneTAG Technology, Inc. specializes in developing DNA Detection Switch (DDS) probe systems for real-time PCR that use labeled probes and competitive, quencher-labeled antiprobes. Our novel probe systems enable unparalleled single-based discrimination (iDDS probes), error-checking amplification (ZIPR probes), or allele-specific amplification (Wild Terminator [WTx] blocking probes). The Specific Aims of this Phase I application are 1) to develop DDS/WTx probe assays for IDH1 and IDH2 mutants found in glioma, and 2) to test for IDH1 and IDH2 mutations in plasma DNA samples from glioma patients. Experiments will be performed with synthetic DNA templates and deidentified, blinded plasma DNA from glioma patients (provided by our collaborators at Emory Hospital). Successful completion of this proposal will justify subsequent Phase II validation studies in preparation for filing for FDA approval. Currently, no FDA-approved blood test is available for detecting IDH1 and IDH2 mutations. Developing a non-invasive approach to detect IDH mutations will enable routine testing for early detection of activating mutations and serve as a stepping stone for generating other tests for cancer biomarkers or drug-resistance mutations.
