Project 4: Therapeutic Mechanisms of Co-Targeting of EGFR and Src Family Kinases
Jennifer R. Grandis, MD, Project Leader
Ann Marie Egloff, PhD, Co-Investigator
Projects 2 and 3 have explored the roles of STAT3 and an epidermal growth factor receptor (EGFR)-specific immune response, respectively, in the response of head and neck squamous cell carcinoma SCCHN to cetuximab therapy. This project investigates what therapeutic benefits lie in co-targeting of oncogenic pathways that are activated in the setting of EGFR blockade in conjunction with cetuximab administration.
This project was derived from earlier research focused on elucidating interactions between G-protein-coupled receptors (GPCR) and EGFR in SCCHN, with the long-term goal of designing a clinical trial combining EGFR and GPCR inhibitors for head and neck cancer patients. Earlier research demonstrated the critical role of Src family kinases (SFK) in GPCR-induced EGFR activation, and, in the absence of a pan-GPCR inhibitor for clinical use, the investigators have elected to refocus this project on co-targeting of SFK and EGFR.
New preliminary data also implicates activation of c-Met in the setting of EGFR resistance or blockade. Our working hypothesis is that persistent signaling through alternate kinases in the setting of EGFR blockade contributes to the limited clinical responses to EGFR targeting in SCCHN. The overriding hypothesis is that there are defined alternative pathways that bypass a cancer cell's need for EGFR signaling, and represent potential targets for combination therapy.The two candidates we have identified are SFK and c-Met.
Completion of these studies will elucidate mechanisms of resistance to EGFR targeting strategies, thus facilitating the design of therapeutic regimens to enhance clinical response. The project's specific aims are:
To determine the anti-tumor mechanisms of inhibition of Src family kinases in SCCHN preclinical models of EGFR inhibitor resistance.
These studies will test the hypothesis that co-inhibition of EGFR and Src kinases leads to enhanced anti-tumor effects compared with strategies that target either pathway alone in SCCHN models of resistance to cetuximab and/or erlotinib.
To determine the role of HGF/c-Met signaling in mediating resistance of SCCHN to EGFR inhibition and/or as an alternative target for SCCHN therapy.
These studies will test the hypothesis that activation of c-Met contributes to head and neck cancer tumorigenesis and to resistance to EGFR inhibition where c-Met targeting strategies may have therapeutic benefit in SCCHN alone or in combination with EGFR inhibitors.
To examine the biomarker correlates of cetuximab plus dasatinib in SCCHN patients.
In the Phase II trial, patients who have been previously treated with cetuximab will receive a loading dose of cetuximab followed one week later by the addition of dasatinib, thereby providing an opportunity to study the ability of dasatinib to enhance the clinical response to cetuximab in patients who have previously been treated with this EGFR targeting agent. Pathways identified in preclinical models in Aims 1 and 2 will be analyzed in the tissues from the subjects enrolled in this trial.