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Development of Small Molecule Inhibitors and Biologic Agents for Treatment of Glioblastoma Using Intracerebral Microdialysis and Signatures of Vulnerability

Award Number: U19CA264512
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY - OVERALL The overall goal of this Glioblastoma (GBM) Therapeutics Network (GTN) U19 application from City of Hope, Translational Genomics Research Institute, and University of Alabama at Birmingham is to develop superior treatments for patients with GBM, the most common and aggressive primary brain tumors in adults. Effective treatments remain elusive and patients are rarely cured with standard therapies. This GTN U19 application embodies a unique combination of approaches designed to significantly advance the treatment of patients with GBM by addressing tumor heterogeneity, blood-brain barrier penetration, and the immunosuppressive GBM tumor microenvironment. The three proposed research projects will translate therapeutic agents from preclinical development, through IND-enabling studies, and into phase I clinical studies in adult patients with GBM. Each project is based on novel molecular preclinical studies with small-molecule inhibitors and immunomodulatory agents that use signature-guided assessment and treatments. Specific goals of the projects are: Project 1. Develop and clinically test an engineered oncolytic herpes virus expressing a full- length anti-CD47 monoclonal antibody for treatment of GBM. Project 2. Develop and clinically test tasquinimod as an adjunct to enhance the efficacy of anti-GBM immunotherapies administered peri-operatively. Project 3. Develop and clinically test a molecular “signatures of vulnerability” guided treatment of GBM with neddylation inhibitor pevonedistat. In addition, this U19 application proposes strategies that will address major barriers in drug development by incorporating two innovative research tools: 1) intracerebral microdialysis to rationally select appropriate systemically administered therapies for testing in GBM patients and 2) next generation exome and transcriptome sequencing to identify molecular “signatures of vulnerability” that can guide appropriate patient selection for clinical trial enrollment. These analytical capabilities will enable us to quantify CNS drug penetration and dissect genomic heterogeneity in tumor and stromal cells in the proposed clinical trials. Also, two of the proposed projects leverage City of Hope’s GMP facilities to manufacture biological agents and small molecules that will be tested in adult GBM patients for the first time. In summary, the innovative projects and shared resources cores in this application combine our strengths in basic, translational, and clinical research in a highly collaborative setting that promotes the sharing of ideas, results, resources, and clinical populations to develop effective treatments for GBM. If successful, data generated by these studies have the potential to transform the treatment of adult GBM patients by introducing new agents that circumvent tumor heterogeneity and immunosuppression.


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 = $882,648 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	003	4	9/5/2024	NON-COMPETING CONTINUATION	$882,648
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	3	4/30/2024	NON-COMPETING CONTINUATION	$0
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	002	3	6/13/2024	NON-COMPETING CONTINUATION	$0
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	3	3/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $882,648

Issue Date FY: 2023 ( Subtotal = $917,677 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	002	3	9/12/2023	NON-COMPETING CONTINUATION	$917,677
2023	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	2	3/6/2023	NON-COMPETING CONTINUATION	$0
2023	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	2	7/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $917,677

Issue Date FY: 2022 ( Subtotal = $920,861 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	2	9/1/2022	NON-COMPETING CONTINUATION	$920,861
2022	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	1	6/10/2022	NEW	$0
														Subtotal = $920,861

Issue Date FY: 2021 ( Subtotal = $999,063 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	1	9/13/2021	NEW	$999,063
														Subtotal = $999,063

Grand Total All Awards = $3,720,249

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Development of Small Molecule Inhibitors and Biologic Agents for Treatment of Glioblastoma Using Intracerebral Microdialysis and Signatures of Vulnerability

Award Number: U19CA264512

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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