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
Hoadley, Katherine A; Yau, Christina; Wolf, Denise M et al. (2014) Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158:929-44
Du, Jihui; Romano, Rose-Anne; Si, Han et al. (2014) Epidermal overexpression of transgenic ?Np63 promotes type 2 immune and myeloid inflammatory responses and hyperplasia via NF-?B activation. J Pathol 232:356-68
Nottingham, L K; Yan, C H; Yang, X et al. (2014) Aberrant IKK? and IKK? cooperatively activate NF-?B and induce EGFR/AP1 signaling to promote survival and migration of head and neck cancer. Oncogene 33:1135-47
Friedman, Jay A; Wise, Stephanie C; Hu, Michael et al. (2013) HSP90 Inhibitor SNX5422/2112 Targets the Dysregulated Signal and Transcription Factor Network and Malignant Phenotype of Head and Neck Squamous Cell Carcinoma. Transl Oncol 6:429-41
Bian, Y; Hall, B; Sun, Z-J et al. (2012) Loss of TGF-? signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. Oncogene 31:3322-32
Brown, Matthew S; Diallo, Oumou T; Hu, Michael et al. (2010) CK2 modulation of NF-kappaB, TP53, and the malignant phenotype in head and neck cancer by anti-CK2 oligonucleotides in vitro or in vivo via sub-50-nm nanocapsules. Clin Cancer Res 16:2295-307
Cohen, Jonah; Chen, Zhong; Lu, Shi-Long et al. (2009) Attenuated transforming growth factor beta signaling promotes nuclear factor-kappaB activation in head and neck cancer. Cancer Res 69:3415-24
Wang, Frederick; Arun, Pattatheyil; Friedman, Jay et al. (2009) Current and potential inflammation targeted therapies in head and neck cancer. Curr Opin Pharmacol 9:389-95