We prevlously reported that Signal Transducer and Activator of Transcription 3 (STATS) is constitutively activated in SCCHN via EGFR-dependent and EGFR-independent pathways. Moreover, constitutive STATS activation enhances SCCHN survival and induces resistance to EGFR inhibition, suggesting that STATS, and components of the STATS signaling pathway, may serve as important therapeutic targets either alone or in combination with EGFR blockade. In the previous funding period, we demonstrated that activated STATS could be selectively targeted with a double-stranded "decoy" oligodeoxynucleotide (ODN) representing the high affinity serum inducible element (hSIE), where the STATS decoy inhibited the growth of SCCHN in vitro and in vivo. With additional support from the NCI RAID program we demonstrated that the STATS decoy was not toxic in a non-human primate model and manufactured clinical grade STATS decoy. A phase 0 clinical trial was implemented at the University of Pittsburgh to test the biologic effects of the STATS decoy in human SCCHN. We further demonstrated induction of SCCHN cell death via targeted inhibition of Bcl-X{L}, an antiapoptotic Bcl-2 family member whose expression in SCCHN is regulated by STATS and correlates with chemotherapy resistance. New results (see Preliminary Studies) demonstrate the importance of the proteasome in regulating the expression and function of STATS and Bcl-2 family members in SCCHN cells, as well as the proliferation and survival of SCCHN in vitro and in vivo. Based on our preliminary studies, we hypothesize that STATS decoy will decrease expression of STATS target genes in human SCCHN. We further hypothesize that co-targeting of STATS and other components of the EGFR/STATS signaling network (including Bcl-2 family members and the proteasome) will result in enhanced anti-tumor effects.
In Specific Aim 1 we will assess the pharmacodynamics of the STATS decoy in modulating downstream targets in the tumors from subjects enrolled in the ongoing phase 0 trial.
Specific Aim 2 will investigate anti-tumor mechanisms of STATS targeting in combination with inhibitors of the Bcl-2 protein family, the proteasome, and the EGFR. In this Aim we will also evaluate the role of baseline phospho-STATS/total STATS expression in modulating response to treatment with cetuximab plus bortezomib in an ongoing collaborative phase I trial at the University of Pittsburgh and the NCI. This trial represents the first combination of these agents in SCCHN.
Specific Aim 3 will determine the anti-tumor effects of an orally bioavailable compound that blocks STATS, guggulsterone, alone and in combination with blockade of EGFR or the proteasome in SCCHN preclinical models. Collectively, we expect that these studies will allow us to: a) evaluate the effects of STATS decoy in SCCHN patients, b) optimize strategies for co-targeting components of the EGFR/STATS signaling network, and c) test mechanisms of treatment response in SCCHN patients based on findings in our preclinical models.

Public Health Relevance

Cumulative evidence supports STATS as a therapeutic target in head and neck cancer. The studies proposed in this project will determine the pharmacodynamic effects of the first-in-human STATS inhibitor, a transcription factor decoy strategy that we developed in the prior funding period. In addition, we will determine the effects of cotargeting of STATS with other components of its signaling network. Finally, we will test the therapeutic benefit of an orally bioavailable inhibitor of STATS, guggulsterone, in preclinical SCCHN models. These studies will facilitate the development of more effective treatment strategies for head and neck cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097190-10
Application #
8707195
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
$186,479
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Li, Jing; Jie, Hyun-Bae; Lei, Yu et al. (2015) PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res 75:508-18
Johnson, Daniel E (2015) The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors. Endocr Relat Cancer 22:T1-17
Sen, Malabika; Paul, Kathleen; Freilino, Maria L et al. (2014) Systemic administration of a cyclic signal transducer and activator of transcription 3 (STAT3) decoy oligonucleotide inhibits tumor growth without inducing toxicological effects. Mol Med 20:46-56
Parikh, Rahul A; Appleman, Leonard J; Bauman, Julie E et al. (2014) Upregulation of the ATR-CHEK1 pathway in oral squamous cell carcinomas. Genes Chromosomes Cancer 53:25-37
Johnston, Paul A; Sen, Malabika; Hua, Yun et al. (2014) High-content pSTAT3/1 imaging assays to screen for selective inhibitors of STAT3 pathway activation in head and neck cancer cell lines. Assay Drug Dev Technol 12:55-79
Qian, Wei; Wang, Jingnan; Roginskaya, Vera et al. (2014) Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells. Oncotarget 5:4180-94
Klein, Jonah D; Sano, Daisuke; Sen, Malabika et al. (2014) STAT3 oligonucleotide inhibits tumor angiogenesis in preclinical models of squamous cell carcinoma. PLoS One 9:e81819
Peyser, Noah D; Grandis, Jennifer R (2014) Genetic mutations in head and neck cancer: utilizing existing treatments. Pharmacogenomics 15:1553-5
Li, Changyou; Egloff, Ann Marie; Sen, Malabika et al. (2014) Caspase-8 mutations in head and neck cancer confer resistance to death receptor-mediated apoptosis and enhance migration, invasion, and tumor growth. Mol Oncol 8:1220-30

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