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New Therapeutic Approaches for Stratified High-REST GBM Subtype

Award Number: R01NS119162
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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New Therapeutic Approaches for Stratified High-REST GBM Subtype - Summary [Print using Actual size (Acrobat) or Scale: 100% (Preview)] for proper font size (11)] Glioblastoma (GBM), a lethal human brain tumor, is made up of multiple molecular subtypes, suggesting that therapy could be targeted to particular subtypes. Yet all newly diagnosed GBM patients are treated with a similar therapeutic regimen, which results in overall poor patient outcomes. GBM tumors contain stem-like cells (GSCs) that contribute to tumor initiation, growth, and resistance to standard-of-care temozolomide (TMZ) and ionizing radiation (IR). Thus, GSCs present an excellent system in which to study the biology of GBM and develop and evaluate targeted therapeutic approaches to GBM. Our long-term goal is to develop mechanism- based therapeutic approaches to significantly advance the care of GBM patients. Our laboratory discovered the transcriptional repressor REST as a stem cell promoter, and thus a critical oncogenic regulator, in medulloblastoma. We and others discovered that REST also regulates oncogenesis in GBM and that tumors with GSCs expressing high levels of REST (HR-GSCs) are molecularly and biologically distinct from tumors with GSCs expressing low levels of REST (LR-GSCs). Further, GBM patients with an HR tumor transcriptome signature have shorter survival than patients with an LR tumor signature, similar to our results with HR-GSC versus LR-GSC tumors in mouse models. These studies have suggested that REST is a potential therapeutic target in HR-GBM tumors. Yet there is no REST-specific therapeutic approach for stratified HR-GSC tumors. The goal of this project is to determine therapeutic approaches for HR-GSC tumors using mouse intracranial tumor models. First, information obtained here will determine whether targeting HR-GBM tumors with REST- specific inhibitor, REST-VP16, is a valuable therapeutic approach for HR-GBM. Second, Information obtained here will determine whether targeting HR-GBM tumors with REST downstream miR targets via exosome- mediated delivery would promote therapeutic approaches for HR-GBM. Third, we will determine the underlying regulatory network changes and transcriptome signatures in selected tumors with and without treatment conditions. Such regulatory networks will provide information about changes in treatment-dependent downstream pathways and targets. The transcriptome signatures could be useful to measure treatment progression in a clinical setting. Fourth, we will determine the homing mechanism of Exosome-mediated delivery of miRs to HR-tumors. Information obtained here will aid in designing exosomes with enhanced homing capabilities to HR-GBM. Thus, the project has the potential to produce a novel, mechanism-based therapeutic approach for the HR-GBM subtype, for which such approaches are limited.


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 = $0 )
2026	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $364,500 )
2025	2025	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/21/2024	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $364,500

Issue Date FY: 2024 ( Subtotal = $392,850 )
2024	2024	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/1/2023	NON-COMPETING CONTINUATION	$364,500
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/3/2024	NON-COMPETING CONTINUATION	$28,350
														Subtotal = $392,850

Issue Date FY: 2023 ( Subtotal = $405,000 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/1/2023	NON-COMPETING CONTINUATION	$40,500
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/15/2022	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $405,000

Issue Date FY: 2022 ( Subtotal = $405,000 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/12/2022	NON-COMPETING CONTINUATION	$40,500
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/25/2021	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $405,000

Issue Date FY: 2021 ( Subtotal = $405,000 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/15/2020	NEW	$405,000
														Subtotal = $405,000

Grand Total All Awards = $1,972,350

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New Therapeutic Approaches for Stratified High-REST GBM Subtype

Award Number: R01NS119162

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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