Project 2: Inhibition of the STAT3 Signaling Network
Daniel E. Johnson, PhD, Co-Project Leader
Jennifer R. Grandis, MD, FACS, Co-Project Leader
Squamous cell carcinoma of the head and neck (SCCHN) is a leading cause of cancer mortality worldwide, and traditional therapies, including surgery, radiation therapy, and chemotherapy are able to eradicate head and neck cancer in only 50% of cases. Targeting strategies aimed at blocking the epidermal growth factor receptor (EGFR), specifically the monoclonal antibody cetuximab, resulted in modestly improved survival when combined with radiation. However, despite the ubiquitous expression of EGFR in SCCHN tumors, the clinical response rate to cetuximab as single agent therapy is less than 20%. Hence, alternative targeting strategies are needed to complement EGFR blockade.
Previous research from our group has shown that:
- Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively activated in SCCHN via EGFR-dependent and EGFR-independent pathways.
- Constitutive STAT3 activation enhances SCCHN survival and induces resistance to EGFR inhibition, suggesting that STAT3, and components of the STAT3 signaling pathway, may serve as important therapeutic targets either alone or in combination with EGFR blockade.
- Activated STAT3 can be selectively targeted with a double-stranded “decoy“ oligodeoxynucleotide (ODN) representing the high affinity serum inducible element (hSIE), where the STAT3 decoy inhibits the growth of SCCHN in vitro and in vivo.
With additional support from the NCI RAID program, our group demonstrated that:
- The STAT3 decoy was not toxic in a non-human primate model and manufactured clinical grade STAT3 decoy. A phase 0 clinical trial was implemented at the University of Pittsburgh to test the biologic effects of the STAT3 decoy in human SCCHN.
- SCCHN cell death was induced via targeted inhibition of Bcl-XL, an anti-apoptotic Bcl-2 family member whose expression in SCCHN is regulated by STAT3 and correlates with chemotherapy resistance.
- The proteasome is important in regulating the expression and function of STAT3 and Bcl-2 family members in SCCHN cells, as well as the proliferation and survival of SCCHN in vitro and in vivo.
This project hypothesizes, based on our preliminary studies, that the STAT3 decoy will decrease expression of STAT3 target genes in human SCCHN. We further hypothesize that co-targeting of STAT3 and other components of the EGFR/STAT3 signaling network (including Bcl-2 family members and the proteasome) will result in enhanced anti-tumor effects.
This project has 3 specific aims:
- Assess the pharmacodynamics of the STAT3 decoy in modulating downstream targets in the tumors from subjects enrolled in the ongoing phase 0 trial.
- Investigate anti-tumor mechanisms of STAT3 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-STAT3/total STAT3 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.
- Determine the anti-tumor effects of an orally bioavailable compound that blocks STAT3, 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 the STAT3 decoy in SCCHN patients, b) optimize strategies for co-targeting components of the EGFR/STAT3 signaling network, and c) test mechanisms of treatment response in SCCHN patients based on findings in our preclinical models.