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Establishing the clinical utility of cell-free tumor DNA methylation profiling as a reliable liquid biopsy approach in brain tumors

Award Number: R01CA263196
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Establishing the clinical utility of cell-free tumor DNA methylation profiling as a reliable liquid biopsy approach in brain tumors - PROJECT SUMMARY Tumors of the central nervous system (CNS) are the most fatal malignancies. Determining the optimal treatment for patients relies on accurate diagnoses, which at present is only achievable by histopathological analyses of the tissue obtained by invasive brain surgery. Operations in the brain instill tremendous anxiety in patients and pose a significant risk for neurological morbidity and even mortality. In addition, accurate longitudinal monitoring of response to treatment, and distinguishing recurrence from treatment-related effects (pseudoprogression), relies on limited information obtained on radiologic imaging as the option to invasively obtain tissue longitudinally over the course of disease is prohibitive due to the morbidity of repeat procedures. Given these limitations, there has been significant interest in identifying non-invasive or “liquid” biomarkers for the diagnosis of CNS tumors. Most groups have looked at mutations in circulating cell-free tumor DNA in the plasma or cerebrospinal fluid. Unfortunately, CNS tumors usually do not release enough DNA into the systemic circulation for such an approach to be reliable on a prospective clinical basis. Furthermore, searching for single mutations does not allow for the discrimination of the many different types of brain tumors included in a differential diagnosis. Instead of focusing on mutations, we focused on DNA methylation alterations that are highly abundant and cancer specific. We developed, optimized, and validated a novel approach termed cell-free methylated DNA immuno-precipitation and sequencing (cfMeDIP-seq) that involves isolating and enriching for methylated fragments of tumor cell-free DNA using a methylation-specific antibody and then sequencing. Published data from our group provides proof-of-principle that plasma cfMeDIP-seq can reliably and accurately diagnose tumors throughout the body, including those in the CNS. Based on these data, we hypothesize that methylation profiling of circulating DNA, via cfMeDIP-seq, identifies reliable biomarkers for the diagnosis, prognosis, and monitoring of CNS tumors non-invasively. We will build upon our existing data to use cfMeDIP-seq as a novel technique to establish and validate a comprehensive, non-invasive CNS tumor classifier (Aim 1); build an accurate predictive model for the non-invasive prognostication of meningiomas (Aim 2); identify plasma biomarkers of response to treatment, recurrence, and malignant transformation in gliomas (Aim 3); and identify methylation and plasma biomarkers of brain metastases development from systemic cancers (Aim 4). Success in this proposal will genuinely help shape a much-needed paradigm-shift in the field of neuro-oncology by establishing cfMeDIP-seq as a reliable liquid biomarker for the non-invasive diagnosis, prognostication, and monitoring of patients with primary and metastatic CNS tumors.


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: 2026 ( Subtotal = $358,475 )
2026	2026	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	000	5	5/11/2026	NON-COMPETING CONTINUATION	$358,475
														Subtotal = $358,475

Issue Date FY: 2025 ( Subtotal = $391,675 )
2025	2025	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	000	4	4/10/2025	NON-COMPETING CONTINUATION	$352,509
2025	2025	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	001	4	5/22/2025	NON-COMPETING CONTINUATION	$39,166
														Subtotal = $391,675

Issue Date FY: 2024 ( Subtotal = $370,260 )
2024	2024	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$19,484
2024	2024	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	000	3	3/8/2024	NON-COMPETING CONTINUATION	$350,776
														Subtotal = $370,260

Issue Date FY: 2023 ( Subtotal = $400,069 )
2023	2023	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	000	2	3/23/2023	NON-COMPETING CONTINUATION	$400,069
														Subtotal = $400,069

Issue Date FY: 2022 ( Subtotal = $410,441 )
2022	2022	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	000	1	3/21/2022	NEW	$410,441
														Subtotal = $410,441

Grand Total All Awards = $1,930,920

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Establishing the clinical utility of cell-free tumor DNA methylation profiling as a reliable liquid biopsy approach in brain tumors

Award Number: R01CA263196

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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