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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-GRB-I)
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University of Pittsburgh
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Albergotti, William G; Gooding, William E; Kubik, Mark W et al. (2017) Assessment of Surgical Learning Curves in Transoral Robotic Surgery for Squamous Cell Carcinoma of the Oropharynx. JAMA Otolaryngol Head Neck Surg 143:542-548
Jie, Hyun-Bae; Srivastava, Raghvendra M; Argiris, Athanassios et al. (2017) Increased PD-1+ and TIM-3+ TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients. Cancer Immunol Res 5:408-416
Kubik, Mark; Mandal, Rajarsi; Albergotti, William et al. (2017) Effect of transcervical arterial ligation on the severity of postoperative hemorrhage after transoral robotic surgery. Head Neck 39:1510-1515
Patel, Snehal G; Carty, Sally E; McCoy, Kelly L et al. (2017) Preoperative detection of RAS mutation may guide extent of thyroidectomy. Surgery 161:168-175
Srivastava, Raghvendra M; Trivedi, Sumita; Concha-Benavente, Fernando et al. (2017) CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer. Clin Cancer Res 23:707-716
Concha-Benavente, Fernando; Ferris, Robert L (2017) Oncogenic growth factor signaling mediating tumor escape from cellular immunity. Curr Opin Immunol 45:52-59
Walline, Heather M; Goudsmit, Christine M; McHugh, Jonathan B et al. (2017) Integration of high-risk human papillomavirus into cellular cancer-related genes in head and neck cancer cell lines. Head Neck 39:840-852
Andrews, Lawrence P; Marciscano, Ariel E; Drake, Charles G et al. (2017) LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev 276:80-96
Zhong, Qian; Liu, Zhi-Hua; Lin, Zhi-Rui et al. (2017) The RARS-MAD1L1 Fusion Gene Induces Cancer Stem Cell-like Properties and Therapeutic Resistance in Nasopharyngeal Carcinoma. Clin Cancer Res :
Godse, Neal R; Khan, Nayel; Yochum, Zachary A et al. (2017) TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression. Clin Cancer Res 23:7324-7332

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