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Mechanisms of Adenoid Cystic Carcinoma Development and Tumor Maintenance

Award Number: R01DE026735
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Mechanisms of Adenoid Cystic Carcinoma Development and Tumor Maintenance - PROJECT SUMMARY Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. Over 60% of the ACC patients succumb to the disease within 15 years from diagnosis. The lack of reliable experimental models for ACC has limited our progress in understanding the biology of the disease and the proliferation of preclinical studies to test new therapies. In this proposal we address this fundamental need by proposing the generation of genetically engineered mouse models that develop autochthonous ACCs. These mice will help determine the role of molecular alterations frequently found in human ACCs and will generate an in vivo platform for molecular and preclinical studies that will help advance towards more effective therapies to treat ACC patients. MYB is by far the most commonly altered gene in human ACCs, as over 70% of the tumors overexpress MYB-NFIB fusions or the full-length MYB. Our preliminary studies show that MYB overexpression in transgenic mice induces ACCs with long latency, indicating that MYB promotes ACC development, but also suggesting that additional alterations are required for ACC development. Genetic alterations affecting MYB-unrelated genes are found at lower frequencies in human ACCs. Notably, mutations in different genes that are predicted to result in activation of NOTCH signaling, including activating mutations in NOTCH1, were found in 25%-35% of the human ACCs, associated with poor prognosis. Of those, inactivating mutations in the SPEN gene were found in ~20% of the ACCs. SPEN is a transcriptional repressor of NOTCH signaling and functions as a tumor suppressor through NOTCH-dependent and NOTCH-independent mechanisms. Importantly, these mutations co-exist with MYB alterations, but their contribution to ACC development is presently unknown. In this proposal we will analyze the cooperation of MYB with NOTCH activation or SPEN inactivation during ACC development, in mouse models that allow the activation of mutations in salivary glands. The inducible nature of the system used to activate these alterations will allow us to determine whether they are required to maintain tumor growth and to identify mechanisms involved in tumor regression. Analysis of the transcriptomes of the tumors that develop in these mice will allow us to identify MYB-regulated genes and pathways that contribute to ACC development, some of which may be required to maintain tumor growth, and thus could be excellent targets to explore new therapies for ACC.


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 = $0 )
2024	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Oral Diseases and Disorders Research	000	6	7/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $360,916 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Oral Diseases and Disorders Research	001	6	4/21/2022	NON-COMPETING CONTINUATION	$32,811
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Oral Diseases and Disorders Research	000	6	12/14/2021	NON-COMPETING CONTINUATION	$328,105
														Subtotal = $360,916

Issue Date FY: 2021 ( Subtotal = $364,562 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Oral Diseases and Disorders Research	001	5	2/23/2021	NON-COMPETING CONTINUATION	$36,457
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Oral Diseases and Disorders Research	000	5	11/20/2020	NON-COMPETING CONTINUATION	$328,105
														Subtotal = $364,562

Issue Date FY: 2020 ( Subtotal = $364,562 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Oral Diseases and Disorders Research	001	4	2/19/2020	NON-COMPETING CONTINUATION	$36,457
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Oral Diseases and Disorders Research	000	4	12/12/2019	NON-COMPETING CONTINUATION	$328,105
														Subtotal = $364,562

Issue Date FY: 2019 ( Subtotal = $364,562 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Oral Diseases and Disorders Research	002	3	12/11/2018	NON-COMPETING CONTINUATION	$364,562
2019	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	1	12/3/2018	NEW	-$1,949
2019	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Oral Diseases and Disorders Research	001	2	12/3/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,949
														Subtotal = $364,562

Issue Date FY: 2018 ( Subtotal = $370,900 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	1	12/18/2017	NEW	$380,000
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Oral Diseases and Disorders Research	002	2	7/11/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$214,900
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	001	1	7/10/2018	NEW	-$224,000
														Subtotal = $370,900

Grand Total All Awards = $1,825,502

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Mechanisms of Adenoid Cystic Carcinoma Development and Tumor Maintenance

Award Number: R01DE026735

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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