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Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology

Award Number: R01DE030123
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: 12/02/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology - Summary Mucoepidermoid carcinomas (MEC) are the most common type of malignant salivary gland tumor (SGT) with advanced MEC often being fatal due to resistance to conventional therapies. Despite their prevalence in salivary malignancies and occurrence in other tissues throughout the body, a thorough understanding of the key molecular events leading to their development has not been fully elucidated. In fact, the incomplete molecular characterization of SGTs was identified by the NIH/NIDCR as a major roadblock to the creation of new clinical diagnostics and therapies. Thus, a comprehensive understanding of the mechanisms driving MEC development and progression is critical to developing better therapeutic interventions. The Aims of this proposal address these significant knowledge gaps through the seamless integration of expertise, tools, and technologies, assembled by our group to investigate how coordinated regulation of two key signaling pathways by a CRTC1-MAML2 (C1/M2) fusion oncogene regulates differentiation and tumor grade in salivary MEC. The C1/M2 fusion is recognized as a key defining feature occurring in over 50% of MEC cases, which reprograms the CREB transcriptional network to drive tumorigenesis. However, in addition to CREB, our recent work and exciting Preliminary Studies now reveal that the C1/M2 oncoprotein also harbors gain-of-function properties that enable MYC binding and co-activation of the MYC transcriptional network. Mechanistically, our data reveal an etiologic role for C1/M2 in the altered cell heterogeneity associated with advanced salivary MEC, identify IGF-1 signaling as a hallmark of fusion positive MEC, and uncover antagonistic roles for C1/M2-CREB versus C1/M2-MYC in promoting differentiation or de-differentiation, respectively. Moreover, we developed and validated the first autochthonous mouse model of salivary MEC that faithfully mimics the genetic and pathologic features of human disease. Therefore, our central hypothesis states that C1/M2 influences intra- tumoral heterogeneity during salivary MEC development and progression by balancing expression of CREB and MYC transcriptional programs that control cell differentiation. To interrogate the molecular and cellular events that initiate, maintain the malignant state, and mediate response to therapy, we also developed an innovative optical reporter and mouse model that permits longitudinal characterization of tumorigenesis. In Specific Aim 1 we will establish whether IGF-1 regulation promotes MEC tumorigenesis and drug resistance. In Specific Aim 2 we will elucidate the mechanisms governing C1/M2 interactions with MYC and the functional significance of these interactions, and in Specific Aim 3 we will determine the clinical significance of regulating CREB versus MYC in relation to MEC pathology.


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 = $497,737 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Oral Diseases and Disorders Research	001	6	5/1/2025	NON-COMPETING CONTINUATION	$498,468
2025	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	1	1/13/2025	NEW	-$731
														Subtotal = $497,737

Issue Date FY: 2024 ( Subtotal = $492,000 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Oral Diseases and Disorders Research	000	5	4/2/2024	NON-COMPETING CONTINUATION	$451,837
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Oral Diseases and Disorders Research	001	5	6/14/2024	NON-COMPETING CONTINUATION	$40,163
														Subtotal = $492,000

Issue Date FY: 2023 ( Subtotal = $499,583 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Oral Diseases and Disorders Research	002	4	4/3/2023	NON-COMPETING CONTINUATION	$499,583
2023	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Oral Diseases and Disorders Research	004	3	6/27/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$24,395
2023	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	2	12/14/2022	NON-COMPETING CONTINUATION	-$495,063
2023	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Oral Diseases and Disorders Research	001	3	12/15/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$495,063
2023	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	003	1	6/27/2023	NEW	-$24,395
														Subtotal = $499,583

Issue Date FY: 2022 ( Subtotal = $495,063 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	2	4/27/2022	NON-COMPETING CONTINUATION	$495,063
														Subtotal = $495,063

Issue Date FY: 2021 ( Subtotal = $493,947 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	1	6/17/2021	NEW	$493,947
														Subtotal = $493,947

Grand Total All Awards = $2,478,330

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Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology

Award Number: R01DE030123

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: 12/02/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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