Wednesday, January 15, 2025 1/15/2025

Elucidating the epigenetic landscape of neurofibromatosis and development of therapeutic targets

Award Number: R01NS117926
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Neurofibromatosis type 2 (NF2) is an inherited disorder caused by germ line mutations of the NF2 tumor suppressor gene and is characterized by development of schwannomas of the VIIIth cranial nerve. Merlin, the product of the NF2 gene, is also inactivated to a significant extent in sporadic schwannomas, meningioma, ependymoma and mesothelioma. In spite of progress made in the understanding of the disease over the past several years, this has not yet translated into therapies. Thus, there is an urgent and unmet need to develop therapeutic options for NF2 patients. At a molecular level, Merlin has been shown to function as a key regulator of multiple signal transduction pathways including those regulated by small G-proteins and the Hippo/YAP pathway. In an effort to identify therapeutic vulnerabilities in NF2-deficient tumors, we assessed the activity of the BET (Bromodomain and Extra-Terminal domain) protein inhibitors NF2-null Schwann cells. The BET proteins are characterized by the presence of two tandem bromodomains and an extra-terminal domain. The bromodomains can specifically bind acetylated lysine residues on histones, serving as epigenetic readers that decipher the histone acetylation code. Our preliminary data indicate that BET inhibition suppresses the proliferation of NF2- null Schwann and schwannoma cells in culture and tumor growth in vivo, and that this is mediated through inhibition of bromodomain protein 4 (BRD4). Preliminary data indicates that the effects of BRD4 are mediated to a significant extent via regulation of YAP. Importantly, we recently demonstrated that YAP is required for the accelerated proliferation of NF2-deficient Schwann cells and tumorigenesis. The goals of this proposal are to identify the essential functions of BET proteins in Schwann cells and determine whether BET inhibition is a therapeutic approach that should be further developed as a treatment modality for NF2.


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 = $395,445 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/20/2024	NON-COMPETING CONTINUATION	$395,445
														Subtotal = $395,445

Issue Date FY: 2023 ( Subtotal = $411,392 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/23/2023	NON-COMPETING CONTINUATION	$411,392
														Subtotal = $411,392

Issue Date FY: 2022 ( Subtotal = $647,366 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/9/2022	NON-COMPETING CONTINUATION	$423,152
2022	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/29/2021	NEW	$224,214
														Subtotal = $647,366

Issue Date FY: 2021 ( Subtotal = $441,270 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/23/2021	NEW	$441,270
														Subtotal = $441,270

Grand Total All Awards = $1,895,473

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Elucidating the epigenetic landscape of neurofibromatosis and development of therapeutic targets

Award Number: R01NS117926

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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