Abstract A122: Therapeutic modulation of Trkb in head and neck squamous cell carcinoma.

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is a biologically aggressive disease, with an annual incidence of approximately 44,000 cases in the United States, and over 650,000 worldwide. While strides have been made in surgical techniques, refinement of radiation delivery and intensification of local-regional treatment with chemotherapeutic strategies, a significant number of patients succumb to distant metastasis and local-regional failure. Thus, there is a compelling need for new treatment regimens that target relevant molecular pathways. The TRK family of receptor tyrosine kinases (RTK) plays important roles in embryonic development and mediates diverse processes including cellular proliferation, migration, stem cell survival and physiologic angiogenesis. Several lines of evidence support the role of TrkB for invasion and metastasis in various solid tumor models. Our laboratory has established the critical role of the TrkB receptor in human HNSCC tumors and as a mediator of EMT in this disease. TrkB activates diverse downstream signaling cascades that ultimately induce cellular proliferation, invasion and survival mechanisms, through AKT, STAT3 and MAPK pathways. Emerging evidence also supports a role for TrkB in the tumor microenvironment and as a mediator of chemotherapy resistance in HNSCC. Thus, TrkB is a potentially important target for novel treatment approaches for HNSCC. Therapeutic modulation of TrkB function has been supported in the literature by the development of small molecule inhibitors (SMIs) that have putative activity against TrkB but have not resulted in clinical effectiveness. Utilizing computational-based structural modeling, compounds were designed to inhibit the ATP-binding pocket of the TrkB RTK. Synthetic templates were proposed for building a library of potential inhibitors. An induced fit docking protocol was utilized to generate a model capable of evaluating the putative compounds. After an initial model was constructed, the top 20% of scoring structures from docking were evaluated in ten other kinases and the data was fed into a Knime workflow along with ADME calculated properties. The filtering led to 19 structures and the distribution of scores suggests that the selected compound should demonstrate a modest selectivity for TrkB over other kinases and seven of those structures were made and were examined in-vitro. The MTT method was utilized for proliferation analysis in HNSCC cell lines. Proliferation analysis revealed significant growth inhibition for compounds Trk-4 (IC50=3.5) and Trk-5 (IC50=10.4) in all tested HNSCC cell lines. Conclusions: Computational based approaches for the development of TrkB RTK inhibitors are feasible. In vitro validation confirmed the cytotoxic nature of these novel compounds in cell lines with high expression of TrkB. Further validation of efficacy in an animal model and RTK selectivity are warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A122.