Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and also arises in multiple other organ sites. Currently, patients with advanced, unresectable MEC have limited therapeutic options and poor treatment outcomes. We were the first to clone a novel fusion oncogene, CRTC1-MAML2 from a recurrent t(11;19)(q14-21;p12-13) in malignant MEC cells. CRTC1 is a transcriptional co-activator for CREB-mediated transcription with newly discovered roles in metabolism, aging, and cancer, whereas MAML2 is a transcriptional co-activator for the Notch pathway with critical functions in development and cancer. The CRTC1-MAML2 fusion oncogene is associated with more than 50% of human MEC cases and represents a potential major etiologic molecular defect for MEC. Although NCI and NIDCR had identified the development of a mouse model to study CRTC1-MAML2 biology as a high-priority goal, there had been no progress since the First Salivary Gland Cancer Workshop in 2006. The goal of this project is to bridge this significant gap by characterizing the first animal model for CRTC1-MAML2 tumorigenicity. This exciting project will elucidate the role and mechanisms of CRTC1-MAML2 and explore approaches to block downstream oncogenic signals. We previously showed that the CRTC1-MAML2 has strong transcriptional co-activator activity and is capable of transforming epithelial cells in vitro, in art through co-activating the transcription factor CREB. Our recent preliminary studies indicate that depletion of CRTC1-MAML2 fusion expression reduced the growth and survival of human malignant MEC cells when assayed in vitro or when propagated as xenograft tumors in vivo. These findings indicate that CRTC1-MAML2 is essential in maintaining MEC malignant phenotype and thus serves as a promising therapeutic target. A better understanding of the biology of this fusion oncogene will provide new targeting opportunities to block MEC. However, the critical mediators and the in vivo roles of this fusion oncogene in the development and progression of MEC remain poorly elucidated. We have generated exciting, significant preliminary data to support our central hypothesis of this proposal: the CRTC1-MAML2 fusion oncogene has critical roles in MEC pathogenesis through the aberrant activation of target genes and pathways;consequently, the targeting of fusion-induced abnormal signaling is effective in blocking fusion-positive MEC. This hypothesis will be addressed by three specific aims.
Aim 1 will assess the in vivo roles of CRTC1-MAML2 fusion oncogene in MEC tumorigenesis using our newly developed conditional CRTC1-MAML2 mouse model.
Aim 2 will validate the CRTC1-MAML2-regulated target genes and investigate the importance of aberrantly activated CRTC1-MAML2-dependent cell signaling in the maintenance of MEC.
Aim 3 will functionally characterize the novel CRTC1-MAML2/ERR? interaction focusing on its role in regulating tumor angiogenesis. The successful completion of these aims will significantly increase our understanding of the biology of salivary gland tumors, and importantly, may identify novel CRTC1-MAML2-specific therapeutic targets.

Public Health Relevance

The CRTC1-MAML2 fusion oncogene is a specific genetic alteration in mucoepidermoid carcinoma, the most common malignant human salivary gland cancer. We propose to characterize the functions and mechanisms of the CRTC1-MAML2 oncogene and explore approaches to block oncogene functions. Our study will significantly increase our understanding of the biology of salivary gland tumors and identify novel CRTC1-MAML2 oncogene-specific therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE023641-01A1
Application #
8696318
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Venkatachalam, Sundaresan
Project Start
2014-08-08
Project End
2018-05-31
Budget Start
2014-08-08
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$377,458
Indirect Cost
$121,691
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611