Growth Factor Receptor Targeting for Radiosensitization

Over all the past several years, the potential therapeutic targeting of growth factor receptors on tumor cells is an area of active preclinical research and early clinical testing. Two key targets to enhance radiosensitization in human cancers are the epidermal growth factor (EGF) family and vascular endothelial growth factor (VEGF). For a comprehensive dis cussion of these approaches to radiosensitization, the reader is referred to two recent reviews.74,75

The epidermal growth factor receptor family has four transmembrane receptor tyrosine kinases, including HER2, HER3, HER4, and epidermal growth factor receptor (EGFR), which are involved in cell proliferation and survival responses, mediated through ligand binding. EGRF is known to be overexpressed in a majority of several tumors including non-small cell lung cancer, head and neck cancers, and glioblastoma multiforme. Clinical studies confirm that EGRF overexpression is associated with clinical radioresistance in these tumors. HER2 overexpression in breast cancer is also associated with clinical radioresistance. Thus, targeting the EGFR family clearly has the potential for radiosensitization. The preliminary results of a Phase III clinical trial comparing radiation therapy + the chimeric monoclonal antibody against EGRF (Cetuximab, Erbitux; ImClone Systems, New York, NY, and Bristol-Myers Squibb Company, Princeton, NJ, USA) were recently reported showing improved local control and survival at 2 and 3 years.76 Although encouraging, several criticisms in trial design and the lower than expected local control and survival data in the radiation therapy alone, necessitate further clinical testing.

A second developmental area of tumor targeting involves targeting the tumor vasculature. It is recognized that tumor progression during radiation therapy is a major reason for radiation failures. The ability of a tumor to progress during radiation therapy is dependent on the continued formation of new tumor blood vessels. Consequently, by targeting tumor vas-culature, one attempts to disrupt the proangiogenic balance between the tumor and its endothelial and vascular stromal cells.75 Because VEGF is an important proangiogenic tumor growth factor, a considerable amount of emphasis has been placed on VEGF inhibition in preclinical testing with radiation therapy using protein- or receptor-targeted antibodies or using VEGF receptor signaling inhibitors including the cyclooxygenase 2 inhibitors.77

Two other approaches that attempt to target tumor growth and enhance tumor response to ionizing radiation involve targeting tumor oncogenes such as Ras78 and the nuclear transcription factor NF-KB.79 As no clinical data are available on these potential targeted therapies, the reader is referred to two recent reviews of the preclinical research and proposed clinical testing.78,79

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