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Characterizing heterochromatin dysfunction as a driving alteration in cancer

Award Number: R01CA240338
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Characterizing heterochromatin dysfunction as a driving alteration in cancer - PROJECT SUMMARY Recent research has emphatically confirmed that cancer is characterized not only by mutations in genes, but also by disturbances in gene regulation. This latter mechanism often involves chromatin—the proteins and regulatory molecules directly associated with DNA—and their influence on gene expression through so-called “epigenetic” effects. Inactivation of the chromatin regulator protein ATRX (-thalassemia mental retardation X- linked) is commonly seen in several cancer variants, including malignant glioma, the most common and deadly primary brain cancer. While ATRX has been implicated in a variety of biological processes in normal cells, its role in cancer biology is less clear. In our recent work, we confirmed that ATRX deficiency dramatically alters chromatin and underlying gene expression, while also rendering DNA more susceptible to damage, breakage, and other abnormalities. In particular, we found that ATRX loss disrupts the organization of specific regions of chromatin, called heterochromatin, where key developmental genes undergo systematic silencing as organ systems mature. Prior work by other groups suggests that heterochromatin dysfunction, and loss of underlying gene silencing, contributes to cancer development. The central hypothesis of our proposal is that disruptions in heterochromatin promote glioma formation by altering gene expression and inducing damage and abnormalities in DNA. In this project, we will address our central hypothesis using customized human and mouse cell lines that recapitulate the core biological and molecular features of ATRX-deficient glioma, along with bona fide glioma cell lines, with and without ATRX deficiency, derived directly from patients. Some of our studies will incorporate glioma models in mice. Furnished with these reagents, we will conduct epigenetic profiling, coupled with microscopy and molecular and cell biological approaches, to correlate chromatin-related findings with cancerous behaviors. In our first aim, we will characterize the mechanisms by which ATRX deficiency alters heterochromatin in glioma. In our second aim, we will delineate the extent to which heterochromatin dysfunction in ATRX-deficient glioma promotes damage and abnormalities in DNA. Finally, in our third aim, we will identify key gene expression changes associated with ATRX deficiency that drive cancerous behavior in glioma and investigate mechanisms by which they can be therapeutically targeted. If successful, our work will characterize an entirely novel molecular process driving cancer formation and provide insights into treatment strategies for deadly brain tumors.


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 = -$2,745 )
2026	2023	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	5	12/2/2025	NON-COMPETING CONTINUATION	-$2,745
														Subtotal = -$2,745

Issue Date FY: 2023 ( Subtotal = $358,680 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	5	6/23/2023	NON-COMPETING CONTINUATION	$358,680
														Subtotal = $358,680

Issue Date FY: 2022 ( Subtotal = $358,680 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	4	6/24/2022	NON-COMPETING CONTINUATION	$358,680
														Subtotal = $358,680

Issue Date FY: 2021 ( Subtotal = $366,000 )
2021	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	3	7/22/2021	NON-COMPETING CONTINUATION	$366,000
														Subtotal = $366,000

Issue Date FY: 2020 ( Subtotal = $366,000 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	2	7/10/2020	NON-COMPETING CONTINUATION	$366,000
														Subtotal = $366,000

Issue Date FY: 2019 ( Subtotal = $366,000 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	1	7/1/2019	NEW	$366,000
														Subtotal = $366,000

Grand Total All Awards = $1,812,615

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Characterizing heterochromatin dysfunction as a driving alteration in cancer

Award Number: R01CA240338

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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