Signal transduction modulators for cancer therapy: from promise to practice?

Abstract

The Oncologist 2003;8:210-213 www.TheOncologist.com Correspondence: Marinus W. Lobbezoo, Ph.D., NDDO Research Foundation, Amsterdam, The Netherlands. Telephone: 3135-691-0036; Fax: 31-35-691-0052; e-mail: lobbezoo@euronet.nl Received December 12, 2002; accepted for publication January 3, 2003. ©AlphaMed Press 1083-7159/2003/$12.00/0 Cancer cells receive signals from their environment, stimulating them to grow and to proliferate. These signals are carried by autocrine, paracrine, and endocrine growth factors that activate surface receptors on the outside of cells. To translate activation of a membrane-bound receptor into a biological response, the signal generated by receptor activation needs to be carried to the nucleus to trigger protein synthesis. This is achieved by the activation of a cascade of intracellular biochemical reactions, the so-called signal transduction pathways. In cancer cells, elements of signal transduction pathways are often mutated or overexpressed compared with normal cells. Oncogenic gene mutations frequently lead to constitutive activation of signal transduction elements, such as growth factor receptor tyrosine kinases, mimicking a situation of continuous activation of the receptor, even in the absence of the relevant growth factor. Also, more downstream signal transduction elements may be mutated or overexpressed, contributing to the malignant phenotype. The elucidation of signal transduction pathways in cancer cells, both at the proteomic and the genomic levels, has fueled the design of drug molecules intended to act at specific proteins of the signal transduction cascade, often referred to as signal transduction modulators (STMs). STMs may interfere with signal transduction processes by blocking cell surface receptors, inhibiting growth factor receptor tyrosine kinases, or inhibiting the effects of further downstream genes, such as the mitogen-activated protein kinases. Many drug molecules directed against a wide range of signal transduction elements are being evaluated worldwide as potential anticancer therapies (Table 1). Several STMs are currently in clinical trials; others are still in preclinical research and development. Two anticancer drugs, trastuzumab and imatinib, which can be considered STMs, have already received worldwide regulatory approval in several cancer indications. Thus, the area of signal transduction modulation in cancer therapy has reached a state of maturity warranting a dedicated international scientific meeting. The Amsterdam-based NDDO Research Foundation and a number of academic key opinion leaders, including Drs. Bob Pinedo, John Mendelsohn, Jose Baselga, and Bruce Chabner, have joined forces to initiate a series of meetings under the title: International Symposium on Signal Transduction Modulators in Cancer Therapy. The first meeting in this series was held in Amsterdam, September 23-25, 2002, and was very successful in bringing together the world’s leading experts from academia, governmental agencies, and industry [1, 2]. About 350 delegates, representing over 25 countries, attended the twoand-a-half day meeting at the intimate venue of the “Vrije Universiteit” in Amsterdam. They reviewed various aspects of STMs in (experimental) cancer therapy including: