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Intracranial D-2-Hydroxyglutarate as a Monitoring Biomarker for IDH-mutant Glioma.

Award Number: R61NS122096
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Intracranial D-2-Hydroxyglutarate as a Monitoring Biomarker for IDH-mutant Glioma. - ABSTRACT IDH-mutant gliomas are the most common gliomas of young adults. Despite initial sensitivity to chemotherapy and radiation, they invariably progress as treatment resistant lesions to become ultimately fatal. The unique metabolic phenotype of IDH-mutant glioma leaves malignant cells potentially vulnerable to several candidate therapies or therapeutic combination. There remains an urgent unmet need for a reliable quantitative monitoring biomarker to accelerate translational progress Since disease course frequently extends over several years, patient-centric models of therapeutic discovery could leverage reliable surrogate outcomes toward iterative refinement of individualized therapies. This project utilizes a phased, milestone-driven feasibility, discovery (R61; Aims 1-2) and validation analysis (R33; Aims 3-4) of D2-HG as a candidate biomarker of IDH-mutant glioma. This study takes advantage of neurosurgical access to the CNS, wherein CSF access devices utilized for clinical management may be deployed for longitudinal CSF access as an adjunct to lumbar puncture. Moreover, it utilizes tumor-based benchmarks for D2-HG content and production within the tumor based on analysis of tumor tissue and microdialysate. We hypothesize that CSF D2-HG represents a useful monitoring biomarker for IDH- mutant glioma to help quantify response to therapy and identify disease recurrence. To test this hypothesis, we propose the following aims: Aim 1: Determine the technical and biological performance characteristics of CSF D2-HG as a biomarker of IDH-mutant glioma. Detailed and rigorous analyses will be performed for D2-HG and its mass spectroscopy assay including stability, precision, accuracy, interference, and technical as well as biological variance upon repeated measurements and correlates to tumor properties based upon gold-standard benchmarks. Aim 2: Determine a baseline threshold value of CSF D2-HG diagnostic for IDH-mutant glioma and define the minimal percent change indicative of altered disease burden. Appropriate ROC models will be built with and AUC analysis to define a threshold diagnostic of IDH-mutant glioma. Cross-sectional patient cohorts will be used to evaluate responsiveness of D2HG to therapy and disease progression Aim 3: Validate CSF D2HG as a biomarker of therapeutic response. CSF D2-HG will be evaluated longitudinally in to validate responsiveness to therapy as benchmarked modified RANO criteria. Aim 4: Evaluate CSF D2HG as a biomarker of disease progression. A cumulative cross-sectional cohort of patients with verified IDH-mutant gliomas will be followed longitudinally during disease monitoring for recurrent disease to validate the defined threshold indicative of disease progression.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $385,574 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/15/2024	NON-COMPETING CONTINUATION	$357,750
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/3/2024	NON-COMPETING CONTINUATION	$27,824
														Subtotal = $385,574

Issue Date FY: 2023 ( Subtotal = $397,500 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/20/2023	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2022 ( Subtotal = $397,500 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/14/2022	NEW	$397,500
														Subtotal = $397,500

Grand Total All Awards = $1,180,574

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Intracranial D-2-Hydroxyglutarate as a Monitoring Biomarker for IDH-mutant Glioma.

Award Number: R61NS122096

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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