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). The PI3K-CK2 signal kinases are implicated in modulating the reciprocal regulation of REL oncogene and TP53 family tumor suppressor function. 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.

Project Start
Project End
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Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Deafness & Other Communication Disorders
Department
Type
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Moore, Ellen C; Sun, Lillian; Clavijo, Paul E et al. (2018) Nanocomplex-based TP53 gene therapy promotes anti-tumor immunity through TP53- and STING-dependent mechanisms. Oncoimmunology 7:e1404216
Cheng, Hui; Yang, Xinping; Si, Han et al. (2018) Genomic and Transcriptomic Characterization Links Cell Lines with Aggressive Head and Neck Cancers. Cell Rep 25:1332-1345.e5
Morisada, Megan; Clavijo, Paul E; Moore, Ellen et al. (2018) PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation. Oncoimmunology 7:e1395996
Clavijo, Paul E; Moore, Ellen C; Chen, Jianhong et al. (2017) Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells. Oncotarget 8:55804-55820
Xiao, R; Van Waes, C; Schmitt, N C (2017) Putting T cells to work-outsourcing neoantigen detection in head and neck cancers? Oral Dis 23:820-821
Zhang, Yiqun; Kwok-Shing Ng, Patrick; Kucherlapati, Melanie et al. (2017) A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. Cancer Cell 31:820-832.e3
Derakhshan, Adeeb; Chen, Zhong; Van Waes, Carter (2017) Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways. Clin Cancer Res 23:1379-1387
Davis, Ruth J; Moore, Ellen C; Clavijo, Paul E et al. (2017) Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3K?/?. Cancer Res 77:2607-2619
Tran, Linda; Allen, Clint T; Xiao, Roy et al. (2017) Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma. Cancer Immunol Res 5:1141-1151
Chen, Tony; Zhang, Jialing; Chen, Zhong et al. (2017) Genetic alterations in TRAF3 and CYLD that regulate nuclear factor ?B and interferon signaling define head and neck cancer subsets harboring human papillomavirus. Cancer 123:1695-1698

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