The goal of this proposal is to use genomic approaches to identify new therapeutic targets for head and neck squamous cell carcinoma (HNSCC), by defining the p63 pathway in tumors in vivo. The p53 family member p63 is overexpressed in a majority of primary HNSCC tumors and is essential for epithelial precursor development in vivo, suggesting a role for this gene in tumorigenesis. Our recent data using small inhibitory RNA (siRNA) targeted against specific p63 isoforms demonstrates that loss of p63 expression induces apoptosis in HNSCC cells that overexpress p63. In contrast, p63 inhibition has no effect on survival of normal keratinocytes or of tumor cells that do not express p63. To date, the downstream mechanisms of p63 remain poorly characterized. Therefore it will first be determined whether death following p63 inhibition depends on intact function of p53 or the related gene p73, and which p63 isoform(s) provide the survival effect. Second, the downstream genes that mediate tumor-associated effects of p63 will be identified using expression profiling following p63-specific siRNA in HNSCC cells. To confirm putative p63 targets in vivo, microdissected primary tumors from the MGH/MEEI tumor bank will be used to correlate p63 levels with genome-wide expression profiles in primary HNSCC specimens. Comparison of genes regulated following p63 siRNA to genes expressed coincident with p63 in primary tumors should allow identification of the most biologically relevant p63 targets. Third, the potential therapeutic relevance of the confirmed p63 targets will be tested directly in HNSCC using an siRNA approach. Together these studies will define the relevance of the p63 pathway in tumorigenesis, and will identify potential new therapeutic targets that mediate the critical survival effect of p63 in HNSCC. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015945-02
Application #
6877965
Study Section
Special Emphasis Panel (ZDE1-PZ (15))
Program Officer
Shirazi, Yasaman
Project Start
2004-04-01
Project End
2009-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$393,750
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Ellisen, Leif W (2018) Cognitive Computing to Guide Molecular-Based Therapy Selection: Steps Forward amid Abundant Need. Oncologist 23:145-146
Saladi, Srinivas Vinod; Ross, Kenneth; Karaayvaz, Mihriban et al. (2017) ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis. Cancer Cell 31:35-49
Rodriguez Calleja, Lidia; Jacques, Camille; Lamoureux, Fran├žois et al. (2016) ?Np63? Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGF?-Induced Metastasis. Cancer Res 76:3236-51
Isakoff, Steven J; Mayer, Erica L; He, Lei et al. (2015) TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer. J Clin Oncol 33:1902-9
McBride, Sean M; Rothenberg, S Michael; Faquin, William C et al. (2014) Mutation frequency in 15 common cancer genes in high-risk head and neck squamous cell carcinoma. Head Neck 36:1181-8
Forster, Nicole; Saladi, Srinivas Vinod; van Bragt, Maaike et al. (2014) Basal cell signaling by p63 controls luminal progenitor function and lactation via NRG1. Dev Cell 28:147-60
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
Gallant-Behm, Corrie L; Ramsey, Matthew R; Bensard, Claire L et al. (2012) ?Np63? represses anti-proliferative genes via H2A.Z deposition. Genes Dev 26:2325-36

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