iDDS probes detecting IDH mutants in brain cancer

DESCRIPTION provided by applicant Glioblastoma accounts for 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 years Without prior knowledge of a patientandapos 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 IDH and IDH genes are observed in up to of grade II and III oligodendrogliomas astrocytomas and secondary glioblastomas but only occur in andlt of primary glioblastomas Several IDH and IDH point mutations can promote the conversion of the normal metabolic product a ketoglutarate to the oncometabolite D hydroxyglutarate IDH or IDH mutations in glioma patients are predictive of improved overall survival and progression free survival compared to glioma patients with wild type WT IDH and IDH Patients with mutant IDH 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 IDH and IDH are currently being investigated in clinical trials Thus knowing a patientandapos s IDH and IDH 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 to develop DDS WTx probe assays for IDH and IDH mutants found in glioma and to test for IDH and IDH 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 IDH and IDH 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 PUBLIC HEALTH RELEVANCE Glioblastoma is the most common and malignant form of glioma accounting for nearly of all brain tumors Primary glioblastomas show rapid disease progression whereas secondary glioblastomas originate as low grade astrocytomas that form grade IV gliomas over a period of years Differentiating between primary and secondary glioblastoma is challenging since both forms are histopathologically similar however this distinction is critical for accurate prognosis and treatment decisions Mutations in the IDH and IDH genes serve as reliable biomarkers for secondary glioblastoma although detecting these mutations currently requires invasive sampling Recent studies have shown that degraded tumor DNA is present in the blood of glioma patients The overall goal of this Phase I application is to develop a simple blood test to detect low frequency IDH and IDH mutations using a combination of our novel probe systems that provide greater specificity and sensitivity Completion of this project will justify Phase II validation studies in preparation for FDA approval This will provide a public health benefit by enabling a non invasive test for IDH and IDH mutations occurring in brain cancer