E G F R

Targeted molecular imaging - the role of Epidermal Growth Factor Receptors (EGFR) in cancer therapy.

EGFR targeted therapy is already clinically utilized, however this treatment requires careful monitoring since it is effective only in less than one third of the patients.

A precise in vivo evaluation of the EGFR presence and density in various tumors is only possible by further preclinical investigations in animal models and clinical studies utilizing PET labeled biomarkers. In this context, we have pioneered this research endeavor.

Epidermal growth factor (EGF) and erb-2 (HER-2) kinase receptors are among growth factor receptor kinases which play a major role in cancer initiation, development and progression.  Overexpression of the epidermal growth factor receptor has been linked to the malignant transformation of cells and is correlated with invasiveness and poor prognosis in patients.  Thus, the EGFR is an attractive target for the design and development of compounds that can specifically bind to the receptor, and inhibit its tyrosine kinase activity and its signal transduction pathway in cancer cells.

(ZD 1839 , Gefitinib) was ÒThe EGFR reversible inhibitor, Irresa recently approved by the FDA for treatment of Non-small–cell-lung cancer (NSCLC) and prostate cancer, and several other anti-EGFR targeted molecules, such as Tarceva (OSI-774 , Erlotinib) and the anti-EGFR antibody Erbitux , are presently undergoing clinical phase 3 trials.

Gefitinib binds at the ATP site and inhibits the kinase activity of EGFR and has been in clinical use since 2002 for the treatment of NSCLC, but is effective only in a small percentage of patients, in whom EGFR possesses activating mutations in the kinase domain.  Erlotinib yielded similar results to Gefitinib. In the absence of accurate measurements of EGFR phosphorylation in the human tumor, it is actually not possible to assess whether the poor response to Gefitinib and Erlotinib is indeed due to lack of the specific activating mutations, the absence of a survival function of EGFR, or to insufficient long-term occupancy of the receptor.

Consequently, there has been a growing interest in the use of EGFR-TK inhibitors as labeled biomarkers for molecular imaging of EGFR overexpressing tumors by a nuclear medicine modalities such as Positron Emission Tomography (PET). Such imaging studies will contribute to the understanding of molecular biology mechanism of cancer. In a pioneered scientific work, and in collaboration with Prof. Levitzki, we have developed more than 20 EGFR inhibitors labeled with either [I-124], [F-18], [C-11] radioisotopes and evaluated the potential role of EGFR as a specific target for cancer imaging and therapy by in vitro and in vivo methods using our own developed two tumor-bearing animal models. The next steps in this study are to perform several Micro-PET experiments with our animal model under different conditions (dose, time frame, blocking experiment with potential new or existing drugs etc.) in order to identify the best tracer, to evaluate drug potency, to correlate treatment response with EGFR occupancy, and to initiate human studies during 2006.

Since the results from our research have proven to be successful, we have been contacted by several scientific groups in the U.S. (M.D. Anderson, Washington University), Europe (University of Bologna Medical School) and Australia (Ludwig Institute, Melbourne) for the opportunity to collaborate with us.