The long-term objective of this project is to identify new, more effective, and less toxic therapies for Head and Neck Squamous Cell Carcinoma (HNSCC) and related cancers, by understanding the function and regulation of the p53 family members p63 and p73. The p53 family of proteins plays a key role in the pathogenesis of HNSCC. The p53 gene itself is a target of mutational inactivation in more than 50% of these tumors, and p53-mutant tumors are highly lethal regardless of treatment modality. In contrast, the related family member p63 is not mutated but is dramatically overexpressed and/or subject to genomic amplification in the majority of cases. A contribution of p63 to HNSCC is further supported by the essential role we and others have demonstrated for p63 in promoting proliferation, adhesion signaling, and regenerative potential during normal epithelial development. In HNSCC cells p63 also functions as a repressor of apoptosis mediated by the related family member p73. Pro-apoptotic p73 itself is overexpressed particularly in p53-mutant HNSCC, and p63 suppresses apoptosis in these tumors through both physical association with p73 and direct binding to regulatory elements within p73-regulated pro- apoptotic genes. The physiologic significance of these observations is supported by the demonstration that p63/p73 are direct mediators of chemosensitivity in HNSCC which is abrogated by Bcl-2 up-regulation, a mediator of therapeutic resistance. Taken together, these findings provide a strong rationale for further studies to understand the biochemical regulation and functional contribution of p63/p73 in HNSCC. This proposal describes a systematic approach to uncovering the regulation of p63/p73 and their role in tumor maintenance in vivo. We hypothesize that a subset of p63/p73 regulators functions as endogenous apoptosis suppressors in HNSCC. We have conducted a genome wide-screen to identify such regulators, complemented by biochemical studies to identify direct p63-associated transcriptional regulators.
In Aim 1 we will perform proof-of-principle studies for targeting chromatin in HNSCC based on our identification of essential p63 transcriptional co-factors.
In Aim 2 we will validate additional p63-associated co-factors which we hypothesize to mediate distinct transcriptional programs relevant to tumor progression.
In Aim 3 we will test the contribution of these transcriptional programs directly using a genetically engineered mouse HNSCC model.
In Aim 4 we will focus on mining our original screen for new p63-regulators, performing direct validation of the most attractive candidates, correlating their expression with clinical outcome in primary tumor specimens, and performing biochemical studies to determine their mechanism. In addition to improving our knowledge of the basic biology of HNSCC, these studies will advance the goal of uncovering novel and viable therapeutic targets to improve treatment outcomes in this disease.

Public Health Relevance

Head and Neck Squamous Cell Carcinoma (HNSCC) is a common form of human cancer for which little progress has been made in long-term treatment outcomes over the last 30 years. This project aims ultimately to improve treatment success in HNSCC and related tumors, by identifying molecular pathways that function as the tumor cell's Achilles'heel. Once we identify these pathways we will then determine the most promising targets for new cancer therapies, using a variety of experimental tumor model systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015945-09
Application #
8291195
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Venkatachalam, Sundaresan
Project Start
2004-04-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$432,361
Indirect Cost
$182,361
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Zhao, Rui; Fallon, Timothy R; Saladi, Srinivas Vinod et al. (2014) Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev Cell 30:151-65
He, Lei; Torres-Lockhart, Kristine; Forster, Nicole et al. (2013) Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma. Cancer Discov 3:324-37
Ramsey, Matthew R; Wilson, Catherine; Ory, Benjamin et al. (2013) FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma. J Clin Invest 123:3525-38
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Ory, Benjamin; Ellisen, Leif W (2011) A microRNA-dependent circuit controlling p63/p73 homeostasis: p53 family cross-talk meets therapeutic opportunity. Oncotarget 2:259-64
Ory, Benjamin; Ramsey, Matthew R; Wilson, Catherine et al. (2011) A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma. J Clin Invest 121:809-20
Michaud, William A; Nichols, Anthony C; Mroz, Edmund A et al. (2009) Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma. Clin Cancer Res 15:1645-54
Leong, Chee-Onn; Vidnovic, Nick; DeYoung, Maurice Phillip et al. (2007) The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J Clin Invest 117:1370-80
Deyoung, M P; Ellisen, L W (2007) p63 and p73 in human cancer: defining the network. Oncogene 26:5169-83

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