Molecularly targeted therapeutics are being developed to selectively inhibit signal transduction pathways that drive uncontrolled tumor proliferation. However, it is becoming increasingly clear that only those tumors which are dependent on a specific pathway for proliferation will be sensitive to inhibition of that pathway. Thus, there is significant interest in developing methods for identifying patients with sensitive or resistant tumors that would enable clinicians to match individual patients with the most efficacious therapeutic agents and regimen. Unfortunately, the targeted signaling pathways are complex, and progress in identifying molecular predictors of response has been slow. We hypothesize that functional imaging of tumor proliferation before and after a short course of drug therapy can be used to identify tumors that are sensitive or resistant to a specific treatment regimen. 3-deoxy-3-[18F]-fluorothymidine (18F-FLT) is being developed as a proliferation- specific positron emission tomography (PET) radiotracer, and we and others have demonstrated that inhibitors of the epidermal growth factor receptor (EGFR) markedly suppress F-FLT tumor uptake within 48 to 72 hours of starting treatment in animal models. These data suggest that FLT PET imaging could be used to rapidly identify tumors that are responding to EGFR inhibitor treatment. Treatment with the therapeutic anti-EGFR antibody cetuximab significantly improves the efficacy of radiation or cisplatin, and the triple combination of radiation, cisplatin and cetuximab is now being tested in several large randomized trials. In the current application, head and neck cancer patients enrolled on a prospective trial of this combination will be imaged at multiple time points with PET. Although tumor proliferation correlates more closely with FLT uptake than 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake, 18F-FDG PET is routinely used for head and neck cancer staging. Therefore, we will compare FLT and FDG PET for monitoring treatment response. PET imaging and tumor biopsies are required before and after a run-in of cetuximab alone, and we hypothesize that cetuximab-induced suppression of proliferation and EGFR signaling will correlate more closely with changes in F-FLT uptake as compared to F-FDG uptake. The pre- and post-treatment biopsies will be used to study the molecular mechanisms responsible for suppression of FLT uptake following drug therapy. PET imaging also will be performed half-way through radiotherapy to test whether the extent of 18F-FLT (or 18 F-FDG) uptake suppression is predictive for ultimate local control. The proposed studies are directly responsive to PA-05-144, PA-04-045 and PA-04-155, and if this study demonstrates the proof-of-concept that FLT PET can be used to predict response early during a course of therapy, then this approach could integrate into an individualized approach to cancer therapy. Molecularly targeted therapeutics are efficacious only in those tumors which are dependent on a specific pathway for tumor growth or maintenance. The focus of this application is to test whether FLT PET imaging could be used to identify tumor response to a targeted therapy within days of starting treatment. If successful, this approach would facilitate the selection of the most efficacious therapies for individual patients. ? ? ?
