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Role of RBBP4/p300 Complex in Recovery from therapy induced DNA damage in glioblastoma

Award Number: R01CA233522
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: 06/30/2026

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Role of RBBP4/p300 Complex in Recovery from therapy induced DNA damage in glioblastoma - PROJECT SUMMARY Temozolomide (TMZ) chemotherapy is a key component of treatment for patients with newly diagnosed glioblastoma (GBM) and provides clinically meaningful survival benefits. Cytotoxicity from TMZ results from failure to repair TMZ-induced DNA methylation adducts. During replication, these lesions ultimately result in replication fork collapse associated with DNA double strand breaks that are critically repaired by homologous recombination (HR). In this context, we recently discovered that retinoblastoma binging protein 4 (RBBP4) functions in a complex with histone acetyltransferase p300 (p300) as a epigenetic writer to key DNA repair processes including six key HR genes (RAD50, BRCA1, BARD1 BRIP1 FIGNL1, and RAD51) that play different roles in HR pathway. Specifically, knockdown of either RBBP4 or p300 in glioma cell lines and GBM patient-derived xenograft (PDX) models results in marked suppression of these six gene products, impaired HR activity associated with enhanced sensitivity to PARP inhibitors, and dramatically enhanced sensitivity to TMZ in animal models. Downstream of RBBP4/p300 complex, bromodomain and extraterminal domain (BET) family members (BRD2, BRD3, BRD4) function as key readers of p300-mediated acetylation marks to drive gene expression. Based on this and our preliminary data, we hypothesize that the RBBP4/p300/BRD axis is a key regulator of HR efficiency and is a promising pharmacologic strategy for developing a robust, novel, TMZ- sensitizing strategy. There are both p300- and dual p300/BET-inhibitors now entering clinical testing in oncology, which highlight the importance of fully understanding how this complex functions to regulate DNA repair. We will explore this concept in a series of three specific aims: Aim 1: Define the role of RBBP4/p300 in regulation of HR genes. We will extend our initial observations in GBM43 to define the regulation of HR genes across multiple GBM models by this complex. Aim 2: Evaluate the impact of RBBP4/p300 on DNA repair proficiency. We hypothesize that coordinated suppression of multiple HR genes associated with disruption of RBBP4/p300/BET function results in profound HR suppression and TMZ sensitizing effects as compared to modulation of only one component of HR. Aim 3: Define the impact of targeting the p300/BRD4 axis on therapy response in GBM We will test the efficacy of p300 and p300/BET inhibitors alone and in combination with TMZ in PDX models. Ultimately, these studies are designed to provide a strong rationale to pursue these inhibitors in clinical trials for GBM.


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: 2027 ( Subtotal = $0 )
2027	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Cause and Prevention Research	000	6	10/14/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $332,704 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	004	6	7/1/2024	NON-COMPETING CONTINUATION	$343,736
2024	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	002	2	2/2/2024	NON-COMPETING CONTINUATION	$0
2024	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	2	1/4/2024	NON-COMPETING CONTINUATION	$0
2024	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	003	2	3/18/2024	NON-COMPETING CONTINUATION	-$11,032
2024	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	001	2	1/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $332,704

Issue Date FY: 2023 ( Subtotal = $365,624 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	005	5	6/16/2023	NON-COMPETING CONTINUATION	$354,592
2023	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	003	3	11/18/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$2,134
2023	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	004	2	1/27/2023	NON-COMPETING CONTINUATION	$11,032
2023	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	2	10/19/2022	NON-COMPETING CONTINUATION	-$2,134
2023	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	002	2	11/18/2022	NON-COMPETING CONTINUATION	$2,134
2023	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	001	3	10/19/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,134
														Subtotal = $365,624

Issue Date FY: 2022 ( Subtotal = $354,592 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	002	4	7/28/2022	NON-COMPETING CONTINUATION	$354,592
2022	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	001	3	5/20/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$216,739
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	2	5/20/2022	NON-COMPETING CONTINUATION	-$216,739
														Subtotal = $354,592

Issue Date FY: 2021 ( Subtotal = $363,827 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	2	7/1/2021	NON-COMPETING CONTINUATION	$363,827
														Subtotal = $363,827

Issue Date FY: 2020 ( Subtotal = $364,031 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	1	9/19/2020	NEW	$364,031
														Subtotal = $364,031

Grand Total All Awards = $1,780,778

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Role of RBBP4/p300 Complex in Recovery from therapy induced DNA damage in glioblastoma

Award Number: R01CA233522

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: 06/30/2026

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