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Cell of Origin and the Roles of Tumor Microenvironment in Neurofibroma Development and Therapeutics

Award Number: R01CA166593
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/03/2012
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Cell of Origin and the Roles of Tumor Microenvironment in Neurofibroma Development and Therapeutics - Project Summary: Neurofibromatosis type 1 (NF1) is a genetic disorder that affects around 1:3000 live births. While the disease has nearly 100% penetrance in patients, NF1 has a diverse spectrum of manifestations. Hallmark traits of the disease include café-au-lait macules, cutaneous neurofibromas (cNF), plexiform neurofibromas (pNF) and malignant peripheral nerve sheath tumors (MPNST), among other symptoms. In NF1 patients, cNFs usually arise at puberty and beyond, can range widely in size and number, and can cause itching, pain, superficial infections as well as psychosocial and cosmetic burdens. Currently, there is no approved therapeutic option for cNFs aside from elective surgery. The development of new therapeutic approaches for cNF will require an understanding of the cNF cellular origin that can be used to elucidate mechanisms that underpin cNF formation and growth. While biallelic inactivation of NF1 in neoplastic Schwann cells is essential for cNF formation, it is not sufficient, pointing to the critical roles of other genetic or epigenetic changes as well as extrinsic signals from other cell types in the tumor microenvironment. While the field has made significant inroads towards our understanding of these tumors, there are still gaps in our knowledge of cNF pathogenesis that could be addressed by the adoption of a systemic approach to decipher all the biological steps in cNF development from the cell of origin to tumor stage to identify the “rate limiting step” that can be therapeutically targeted to prevent or delay cNF formation. Therefore, in this application, we propose a set specific aims to fill this knowledge gap: We will define the identity of the cNF cell of origin in mice that will guide us to identify the cells of origin for human cNF. We will next decipher how the cell of origin and the tumor microenvironment contribute to drive cNF initiation that will uncover its pathogenesis to delineate biological steps and mechanisms in tumor development as well as generating of preclinical models system that elucidate cNF biology and enable preclinical therapeutic testing.


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 = -$21,008 )
2025	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	002	11	12/4/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$21,008
2025	2022	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	10	10/9/2024	NON-COMPETING CONTINUATION	-$8,111
2025	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	11	10/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$8,111
														Subtotal = -$21,008

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	11	4/12/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$211,295
2024	2022	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	10	4/12/2024	NON-COMPETING CONTINUATION	-$211,295
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $377,055 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	10	7/22/2022	NON-COMPETING CONTINUATION	$377,055
														Subtotal = $377,055

Issue Date FY: 2021 ( Subtotal = $451,616 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	9	8/13/2021	NON-COMPETING CONTINUATION	$384,750
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	001	9	8/24/2021	SUPPLEMENT FOR EXPANSION	$66,866
														Subtotal = $451,616

Issue Date FY: 2020 ( Subtotal = $451,616 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	8	7/13/2020	NON-COMPETING CONTINUATION	$451,616
														Subtotal = $451,616

Issue Date FY: 2019 ( Subtotal = $440,073 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	7	7/16/2019	NON-COMPETING CONTINUATION	$373,207
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	001	7	8/13/2019	SUPPLEMENT FOR EXPANSION	$66,866
														Subtotal = $440,073

Issue Date FY: 2018 ( Subtotal = $384,749 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	001	6	8/3/2018	COMPETING CONTINUATION	$384,750
2018	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	5	6/19/2018	EXTENSION WITH OR WITHOUT FUNDS	-$1
														Subtotal = $384,749

Issue Date FY: 2016 ( Subtotal = $329,925 )
2016	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	5	3/18/2016	EXTENSION WITH OR WITHOUT FUNDS	$329,925
														Subtotal = $329,925

Issue Date FY: 2015 ( Subtotal = $329,925 )
2015	2015	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	4	3/23/2015	NON-COMPETING CONTINUATION	$329,925
														Subtotal = $329,925

Issue Date FY: 2014 ( Subtotal = $320,027 )
2014	2014	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	3	3/27/2014	NON-COMPETING CONTINUATION	$320,027
														Subtotal = $320,027

Issue Date FY: 2013 ( Subtotal = $310,130 )
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	001	2	7/1/2013	NON-COMPETING CONTINUATION	$161,664
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	2	3/11/2013	NON-COMPETING CONTINUATION	$148,466
														Subtotal = $310,130

Issue Date FY: 2012 ( Subtotal = $329,579 )
2012	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	1	5/28/2012	NEW	$329,579
														Subtotal = $329,579

Grand Total All Awards = $3,703,687

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Cell of Origin and the Roles of Tumor Microenvironment in Neurofibroma Development and Therapeutics

Award Number: R01CA166593

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/03/2012

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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