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Developing Therapeutic Strategies for Histone H3.3 Mutant Tumors via Rational Targeting of Specific DNA Repair Pathways

Award Number: R15CA206051
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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Developing Therapeutic Strategies for Histone H3.3 Mutant Tumors via Rational Targeting of Specific DNA Repair Pathways - PROJECT SUMMARY / ABSTRACT The DNA in all eukaryotic cells is wrapped around the four core histone proteins H2A, H2B, H3 and H4 to form nucleoprotein filaments called chromatin. Histones help package the DNA to fit it in the nucleus and regulate access to the genetic information contained within the DNA. Hence, all aspects of DNA metabolism, including DNA damage and repair, as well as diseases such as cancer are likely to be affected by chromatin structure. Improper or inefficient DNA repair is closely linked to cancer formation. Not surprisingly, aberrant chromatin structure or assembly results in genomic instability, which is characterized by the increased rate of acquisition of alterations in the genome and is associated with most human cancers. Chromatin structure and function are regulated by posttranslational histone modifications and sequence variants of the canonical histones present at specific loci or under certain conditions. Recently, certain mutations in the histone variant H3.3 were shown to drive specific cancers such as glioblastomas, chondroblastomas and large cell tumor of the bone, primarily in children and young adults. How H3.3 mutations lead to tumors is unclear, although aberrant transcription due to altered histone modifications are believed to contribute to carcinogenesis. Our preliminary data strongly suggests that H3.3 plays a crucial role in promoting homologous recombination (HR) mediated DNA repair, defects in which are likely to make a strong contribution to carcinogenesis. We find that histone H3.3 is rapidly recruited to sites of laser induced DNA damage in live human cells, whereas the cancer associated H3.3 mutants are defective in this response. Further, H3.3 knockdown results in accumulation of spontaneous DNA damage, enhanced sensitivity to DNA damaging agents and poor recruitment of several HR factors to DNA damage sites. Based on these data, we hypothesize that cells carrying cancer-associated H3.3 mutations are defective in HR and rely on Non-Homologous End Joining (NHEJ) for DNA Double Strand Break (DSB) repair. Hence, inhibition of NHEJ in the presence of DSBs should selectively eliminate H3.3 mutant cancer cells while sparing normal cells. We will test our hypothesis using cell biological assays and a mouse xenograft tumor model along with normal and H3.3 mutant tumor derived cell lines in 3 aims: Aim 1.) Determine the precise role of histone variant H3.3 in DNA DSB repair. Aim 2.) Measure the sensitivity of H3.3 mutant cells to NHEJ inhibitors with/without exogenous DSBs. Aim 3.) Test the efficacy of NHEJ inhibition on H3.3 mutant tumor growth in a mouse xenograft model. Relevance to public health: The studies proposed here will define the role of H3.3 in DNA DSB repair as well as the contribution of DNA repair defects associated with H3.3 mutations to childhood cancers. This will enable a better understanding of the overall contribution of H3.3 in cancer prevention. Moreover, the proposed studies can potentially lead to the development of targeted therapeutic strategies in the near future for H3.3 mutant tumors that would spare non-tumor cells.


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: 2025 ( Subtotal = -$5,720 )
2025	2017	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Cancer Cause and Prevention Research	000	1	5/19/2025	NEW	-$5,720
														Subtotal = -$5,720

Issue Date FY: 2022 ( Subtotal = -$5,720 )
2022	2017	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Cancer Cause and Prevention Research	000	1	12/21/2021	NEW	-$5,720
														Subtotal = -$5,720

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2017	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Cancer Cause and Prevention Research	000	1	11/13/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Cancer Cause and Prevention Research	000	1	2/7/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $429,583 )
2017	2017	FLORIDA STATE UNIVERSITY, THE	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Cancer Cause and Prevention Research	000	1	1/1/2017	NEW	$429,583
														Subtotal = $429,583

Grand Total All Awards = $418,143

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Developing Therapeutic Strategies for Histone H3.3 Mutant Tumors via Rational Targeting of Specific DNA Repair Pathways

Award Number: R15CA206051

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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