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Elucidating and targeting the effects of oncogenic histone mutations

Award Number: K08CA245212
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/10/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Elucidating and targeting the effects of oncogenic histone mutations - PROJECT SUMMARY/ABSTRACT Histone genes are frequently mutated in cancer, but the significance of most histone mutations is unknown and few strategies to therapeutically target tumors harboring histone mutations have been developed. Histones are a fundamental component of chromatin, which regulates the accessibility of DNA for gene expression through dynamically regulated combinatorial post-translational modifications (PTMs) of histones’ N-terminal tails. Classical oncogenic histone (‘oncohistone’) mutations directly prevent the ‘writing’ of some of these PTMs, promoting oncogenesis through altered transcription patterns that inhibit differentiation. The PI and his collaborators have recently characterized an unexpectedly broad landscape of novel oncohistone mutations that occur in roughly 4% of tumors. The goal of the proposed work is to understand the impact of a subset of these novel oncohistones on chromatin and tumor biology and to develop strategies to therapeutically target tumors expressing oncohistones. Preliminary data presented in this proposal show (a) that a class of novel oncohistone mutations at H3 N-terminal arginine (H3R) residues alter nearby regulatory PTMs and impair cellular differentiation, and (b) that differentiation blockade driven by the classical H3K36M oncohistone mutation can be rescued by tyrosine kinase inhibition. Therefore, experiments are proposed to test the hypotheses that H3R oncohistone mutations disrupt the chromatin landscape, alter transcription, and dysregulate cellular functions, and that tyrosine kinase signaling mediates oncohistone-induced differentiation blockade. To rigorously test these hypotheses, experiments are proposed to (1) elucidate the effects of novel oncohistone mutations on the chromatin landscape and chromatin-dependent transcription, differentiation, and tumorigenesis and (2) determine how inhibition of kinase signaling rescues classical oncohistone-induced differentiation blockade. The proposed work will improve understanding of cancer-associated histone mutations and may lead to the development of new genotype-directed cancer therapies. The PI, a Medical Oncology Fellow at Memorial Sloan Kettering Cancer Center (MSKCC), has developed a 5-year career development plan that builds upon his scientific background in chemical biology and clinical training in medical oncology. He will conduct the proposed research under the mentorship of Dr. C. David Allis, an internationally recognized expert in oncohistone mutations and epigenetics, and will develop new skills in chromatin biology including chromatin-relevant bioinformatics and biochemistry that are critical for his future career focused on understanding and therapeutically targeting epigenetically driven cancers. This training, combined with his background, mentorship, and the institutional environment of MSKCC and partner institution The Rockefeller University, positions the PI to successfully transition to independence as an academic physician-scientist with his own laboratory and grant funding.


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	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	000	5	11/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $271,902 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	003	5	8/7/2023	NON-COMPETING CONTINUATION	$271,902
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	000	4	1/9/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	002	4	6/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$118,434
2023	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	001	3	6/15/2023	NON-COMPETING CONTINUATION	-$118,434
														Subtotal = $271,902

Issue Date FY: 2022 ( Subtotal = $271,901 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	001	4	9/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$271,901
2022	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	3	9/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $271,901

Issue Date FY: 2021 ( Subtotal = $273,839 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	3	8/30/2021	NON-COMPETING CONTINUATION	$273,839
														Subtotal = $273,839

Issue Date FY: 2020 ( Subtotal = $273,839 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	2	8/26/2020	NON-COMPETING CONTINUATION	$273,839
														Subtotal = $273,839

Issue Date FY: 2019 ( Subtotal = $273,839 )
2019	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	1	9/10/2019	NEW	$273,839
														Subtotal = $273,839

Grand Total All Awards = $1,365,320

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Elucidating and targeting the effects of oncogenic histone mutations

Award Number: K08CA245212

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/10/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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