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Targeting Glioblastoma with Multifunctional Anti-RAGE Oligonucleotides

Award Number: R01NS143106
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: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Targeting Glioblastoma with Multifunctional Anti-RAGE Oligonucleotides - PROJECT SUMMARY Patients diagnosed with glioblastoma (GBM) have a median overall survival of less than two years even after receiving multimodal therapies. Multiple factors account for treatment resistance including: 1) Inability of therapies to cross the blood-brain barrier to reach invading cells; 2) GBM’s molecular heterogeneity and overlapping escape mechanisms that overcome targeted therapies; 3) Evasive mechanisms that render GBMs resistant to immunotherapy. Therefore, there is an unmet need for GBM treatment approaches that address multiple resistance mechanisms. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily, which was discovered as a transmembrane receptor for the products of nonenzymatic glycation and oxidation of proteins. RAGE is expressed by glioma cells and is activated by ligands present in the GBM tumor microenvironment (TME). Activation of RAGE stimulates multiple signaling pathways that promote GBM progression. Recently, we demonstrated that genetic ablation of intracellular RAGE in gliomas inhibited multiple oncogenic pathways that not only regulate glioma growth and invasion, but also improve the efficacy of immunotherapies by inhibiting galactin-3 production and promoting an immunologically “permissive” TME. Based on these observations, we propose to target RAGE as a multifaceted therapy for GBM. Our central hypothesis is that RAGE inactivation will suppress oncogenic pathways that are important for GBM growth and invasion and enhance responses to immunotherapy. Three aims are proposed to test this hypothesis. Aim 1 will optimize a multifunctional anti-RAGE oligo-based strategy to target GBM. As an alternative approach to blocking RAGE extracellular receptor with small molecules, we propose to inhibit its signaling by optimizing the design of anti-RAGE antisense oligos. The “scavenger” receptor property of RAGE will be exploited to develop multifunctional oligos that are rapidly internalized and selectively silence RAGE signaling in GBM models. Aim 2 will test the in vivo efficacy and determine the mechanism of RAGE ablation in enhancing the anti-tumor immune responses in syngeneic murine GBM models. Findings from this Aim will uncover novel strategies that could enhance immunotherapy efficacy in these resistant tumors. Finally, Aim 3 will assess the combinational effects of anti-RAGE oligos with immunotherapy. In this Aim, we will also perform the pre-clinical studies to optimize the dosing regimen of galactin-3 inhibitors for future GBM clinical trials. To perform this work, we have assembled a multidisciplinary and highly collaborative team with expertise in neuroimmunology, neuro-oncology, and molecular biology. The success of these studies, supported by compelling preliminary data, is expected to lead to the development of novel and critically needed GBM therapies.


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 = $548,395 )
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/1/2026	NEW	$548,395
														Subtotal = $548,395

Grand Total All Awards = $548,395

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Targeting Glioblastoma with Multifunctional Anti-RAGE Oligonucleotides

Award Number: R01NS143106

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: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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