Abstract 1546: Effective co-targeting of tumor and tumor stroma for head and neck cancer treatment: making the right combination

Abstract

Abstract Successful cancer management has been hindered by the development of inherent or acquired resistance. Increasing evidence suggest that manifestation of comparable resistance phenotype may arise from different combinations of molecular lesions. Signal transduction pathways in cancer cells exhibit remarkable flexibility for re-wiring such that cancer cells of solid tumors are able of altering the targeting receptor tyrosine kinases (RTKs) such as EGFR, or using unaffected and co-expressed RTKs signaling, or manifesting gain-of-function changes of the downstream signaling molecules to sustain tumor growth and progression. However, The potential of a “pathway rewiring” strategy to more efficiently target a deregulated signaling network has not been effectively explored due to the lack of scientific framework. Furthermore, the effort of developing effective agents or combinations that can effectively co-target both cancer cells and tumor stroma is lagging behind the therapeutic development aiming at cancer cell targeting. In this report, we demonstrate the effectiveness of integrating predicative pathway analysis to identify mTOR as a key interacting signaling target for developing a rational “pathway-based” combination to overcome resistance to anti-EGFR therapies in squamous carcinoma of the head and neck (HNC). We show for the first time that HNC cancer cells can effectively exploit the molecular interactions between EGFR and mTOR to confer reciprocal resistance. In addition, network modeling and comparison of xenograft with human tumor specimens identifies the abundant presence of myofibroblasts specifically associated with cancer state. We subsequently show the dependence of the clonogenic survival of myofibroblast cells on mTOR signaling in vitro. In vivo, only concomitant inhibition of EGFR and mTOR signaling via erlotinib and rapamycin, respectively, achieves effective differential and co-targeting of cancer cells and myofibroblast and endothelial cell functions in tumor stroma, leading to tumor regression. Thus, we show a systems’ approach-guided biological investigation has the potential to identify resistance mechanisms that can be explored to design more effective combinations of targeted therapies capable of overcoming resistance via “pathway rewiring” and achieving tumor-tumor stroma co-targeting. Based on these observations, an NIH funded network Phase II human clinical trial, lead by the University of Chicago Cancer Center, is soon underway to evaluate the therapeutic efficacy of this combination therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1546.