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Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland Tumor

Award Number: R01DE023641
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: 08/08/2014
PERIOD OF PERFORMANCE END DATE: 11/30/2030

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Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland Tumor - Project summary This competing renewal aims to elucidate how the CRTC1-MAML2 fusion oncogene drives malignancy through tumor-intrinsic mechanisms and immune evasion while evaluating novel therapeutic strategies. CRTC1- MAML2 is a major oncogenic driver of mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. Patients with unresectable, recurrent, or metastatic MEC have poor prognoses and limited treatment options, with no targeted therapies currently available. While immune checkpoint inhibitors (ICIs) have shown some efficacy, responses remain inconsistent. Due to the low prevalence of MEC, large-scale clinical trials are challenging, underscoring the need for a deeper mechanistic understanding to inform new treatment strategies. We originally cloned the CRTC1-MAML2 fusion from a t(11;19) translocation in human MEC cell lines and have since made significant progress in characterizing its oncogenic role. We developed the first genetically engineered mouse model (GEMM) in which a Cre-regulated CRTC1-MAML2 transgene induces salivary gland tumors that recapitulate the histological and molecular features of human MEC. Furthermore, inducible CRTC1- MAML2 knockdown in human MEC xenografts suppressed tumor growth. Mechanistically, CRTC1-MAML2 binds CREB through its CRTC1 CREB-binding domain (CBD) and constitutively activates transcription via its MAML2 transcriptional activation domain (TAD). Disrupting the CRTC1-MAML2/CREB interaction or inhibiting its downstream amphiregulin (AREG)-EGFR signaling suppressed the growth of human MEC cells and xenograft tumors, establishing this fusion-CREB interaction as a key oncogenic driver and a promising therapeutic target. Gene expression profiling reveals that CRTC1-MAML2 silencing or CRTC1-MAML2/CREB disruption not only represses pro-proliferative CREB target genes but also induces a proinflammatory gene signature, suggesting a role in TME modulation. Single-cell RNA sequencing analysis using our GEMM model reveal that CRTC1- MAML2 fosters an immunosuppressive TME. Also, our newly established syngeneic MEC model exhibited resistance to anti-PD1 therapy. Therefore, we hypothesize that CRTC1-MAML2 promotes both tumor-intrinsic growth and TME reprogramming to enable immune evasion. Targeting this fusion axis, alone or in combination with ICIs, may provide more effective therapies for MEC. This hypothesis will be tested by two specific aims. Aim 1 will investigate the role of the CRTC1-MAML2 fusion in MEC tumor progression and immune landscape and Aim 2 will evaluate strategies to inhibit the CRTC1-MAML2 fusion axis alone and with ICI-based immunotherapy. Completion of these aims will provide critical insights into CRTC1-MAML2’s oncogenic function and its dual role in tumor-intrinsic growth and immune evasion. These findings will advance our understanding of MEC biology and guide the development of more effective therapies for CRTC1-MAML2 fusion-positive MEC patients.


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 = $383,750 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	9	2/27/2026	COMPETING CONTINUATION	$383,750
														Subtotal = $383,750

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	8	9/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $354,322 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	8	7/5/2023	NON-COMPETING CONTINUATION	$354,322
														Subtotal = $354,322

Issue Date FY: 2022 ( Subtotal = $351,487 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	7	7/26/2022	NON-COMPETING CONTINUATION	$351,487
														Subtotal = $351,487

Issue Date FY: 2021 ( Subtotal = $355,687 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	6	6/25/2021	NON-COMPETING CONTINUATION	$355,687
														Subtotal = $355,687

Issue Date FY: 2020 ( Subtotal = $356,278 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	002	5	9/16/2020	COMPETING CONTINUATION	$1,029
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	5	7/2/2020	COMPETING CONTINUATION	$356,278
2020	2017	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	001	4	9/16/2020	NON-COMPETING CONTINUATION	-$1,029
														Subtotal = $356,278

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	4	4/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $368,314 )
2017	2017	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	4	5/18/2017	NON-COMPETING CONTINUATION	$368,314
														Subtotal = $368,314

Issue Date FY: 2016 ( Subtotal = $370,204 )
2016	2016	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	3	5/20/2016	NON-COMPETING CONTINUATION	$370,204
														Subtotal = $370,204

Issue Date FY: 2015 ( Subtotal = $376,529 )
2015	2015	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	2	5/4/2015	NON-COMPETING CONTINUATION	$376,529
														Subtotal = $376,529

Issue Date FY: 2014 ( Subtotal = $377,458 )
2014	2014	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	1	8/7/2014	NEW	$377,458
														Subtotal = $377,458

Grand Total All Awards = $3,294,029

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Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland Tumor

Award Number: R01DE023641

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: 08/08/2014

PERIOD OF PERFORMANCE END DATE: 11/30/2030

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