We previously found an association between overexpression of NF-kB related genes, altered expression of TGFb receptor (TBR) subunits and downstream targets in head and neck squamous cell carcinoma (HNSCC). During the prior year we reported that TGFbeta receptor I/ phosphastase tensin (Tgfbr1/Pten) are frequently decreased in HNSCC, and conditional double knockout mice for these genes develop HNSCC that exhibit increased PI3K-Akt pathway and NF-kappaB/REL activation (Bian, Oncogene, 2012). We report the potential of PI3K-mTOR inhibitor for prevention of tumor development in these Tgfbr1/Pten dko mice and therapy of human xenograft bearing mice (Herzog, Bian et al., Clin Cancer Res, 2013). We found that PI3K-mTOR antagonist inhibited downstream progrowth signaling, reactivated tumor suppressor TP53, and sensitized tumors to cytotoxic chemotherapy and radiation. As co-recipients of an NIH Director's Bench to Bedside Award in collaboration with NIDCR investigators, we are conductinga pilot clinical study of neoadjuvant mTOR inhibitor rapamycin in patients with advanced HNSCC (NIH protocol 10-D-180). 10 subjects have been accrued to date. Heat Shock Protein 90 inhibitors target many oncoproteins in the signal network we have shown is co-activated in HNSCC. In collaborative studies, we recently reported that HSP90 inhibitors target overexpressed Epidermal growth factor receptor, downstream signaling, and strongly inhibit human HNSCC xenografts (Ahsan et al., Neoplasia, 2012). We report that HSP90 inhibitor SNX5422/2112 in phase I studies at NIH broadly inhibited oncogenic signal and transcription factors and reactivates wild type p53 in human HNSCC lines and tumor xenograft models (Friedman et al., Translational Oncol, 2013). Inflammation and inflammatory signaling is implicated in promoting cancer development, including human head and neck squamous cell carcinomas (HNSCC). We recently demonstrated that NF-kB transcription factor c-REL interacts with TP53 family members DeltaNp63 and TAp73 to reciprocally activate inflammatory and cancer related genes, while repressing growth arrest and proapoptotic genes in HNSCC (Lu, Cancer res, 2011;Yang, Cancer Res, 2011). Together, these findings suggest signal regulation coordinating NF-kB, p63 and p73 interactions and function may be important in pathogenesis and as targets for prevention and therapy. Candidate kinases regulating NF-kB and TAp73 in SCC cancer stem cells has been identified as potential targets for therapy.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$870,939
Indirect Cost
Name
National Institute on Deafness and Other Communication Disorders
Department
Type
DUNS #
City
State
Country
Zip Code
Si, H; Lu, H; Yang, X et al. (2016) TNF-α modulates genome-wide redistribution of ΔNp63α/TAp73 and NF-κB cREL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer. Oncogene 35:5781-5794
Eytan, Danielle F; Snow, Grace E; Carlson, Sophie et al. (2016) SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2. Cancer Res 76:5442-54
Elghouche, Alhasan; Shokri, Tom; Qin, Yewen et al. (2016) Unilateral Cervical Polyneuropathies following Concurrent Bortezomib, Cetuximab, and Radiotherapy for Head and Neck Cancer. Case Rep Otolaryngol 2016:2313714
Cancer Genome Atlas Network (2015) Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517:576-82
Bian, Yansong; Han, Jiawei; Kannabiran, Vishnu et al. (2015) MEK inhibitor PD-0325901 overcomes resistance to CK2 inhibitor CX-4945 and exhibits anti-tumor activity in head and neck cancer. Int J Biol Sci 11:411-22
Eytan, Danielle F; Snow, Grace E; Carlson, Sophie G et al. (2015) Combination effects of SMAC mimetic birinapant with TNFα, TRAIL, and docetaxel in preclinical models of HNSCC. Laryngoscope 125:E118-24
Hayes, D Neil; Van Waes, Carter; Seiwert, Tanguy Y (2015) Genetic Landscape of Human Papillomavirus-Associated Head and Neck Cancer and Comparison to Tobacco-Related Tumors. J Clin Oncol 33:3227-34
Mohan, Suresh; Vander Broek, Robert; Shah, Sujay et al. (2015) MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma. Clin Cancer Res 21:3946-56
Leiker, Andrew J; DeGraff, William; Choudhuri, Rajani et al. (2015) Radiation Enhancement of Head and Neck Squamous Cell Carcinoma by the Dual PI3K/mTOR Inhibitor PF-05212384. Clin Cancer Res 21:2792-801
Lu, Hai; Yan, Carol; Quan, Xin Xin et al. (2014) CK2 phosphorylates and inhibits TAp73 tumor suppressor function to promote expression of cancer stem cell genes and phenotype in head and neck cancer. Neoplasia 16:789-800

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