"Genomic Analysis as Basis of Novel Cancer Therapy Development: From Herceptin to Sunitinib and beyond..."GCOE Program Seminar(Global Education Seminar)
Cancer represents a disease prototype that is connected to defects in the cellular signaling network that controls proliferation, motility, survival and recognition by the immune surveillance. The first insights into the genetic basis of cancer were obtained by comparing the sequences of retroviral oncogenes with human proto-oncogenens. Currently the spectrum of known genetic alterations in cancer cells includes mutations in various genes leading to structural and functional dysfunctions in signal transmission as well as over- or under-expression of positive or negative signal regulatory proteins respectively.
For the past years we have investigated various aspects of signaling systems in tumor cells in order to identify critical switch points in the pathophysiological process that results in malignancy. These efforts aim at the selective blockade of abnormal, disease-promoting signaling mechanisms by monoclonal antibodies, or small molecule kinase inhibitors rather than the eradication of all growing cells in the body as in the case of most currently used chemotherapeutic drugs. This strategic approach began with the cloning of the EGF receptor cDNA and the related receptor HER-2/neu and translated the animal oncogene concept into target-directed therapy of human cancer. This work yielded the first specific oncogene target-based, FDA-approved (1998) therapeutic agent, “Herceptin”, for the treatment of metastatic breast cancer that is characterized by HER2 overexpression. Subsequent “target-driven drug development” efforts that employed various genomic analysis strategies led to the identification of the receptor tyrosine kinases FGFR4, Axl/Ufo and Flk-1/VEGFR2 as critical signaling elements in tumor progression. The latter served, in cooperation with SUGEN Inc./Pharmacia/Pfizer, as basis for the development of anti-angiogenic small molecule drugs SU5416, SU6668 and SU11248. The drug discovery process that led to SU11248 represents a prototypical example for the adaptation of cancer therapeutics from highly specific to multi-targeted drugs. In January 2006 the FDA approved SU11248/SUTENT for the treatment of Gleevec-resistant GIST and Renal Cell Carcinoma (Pfizer) and on July 19 the European Agency EMEA followed suit.
New developments and insights that were gained over the past twenty years of targeted cancer therapy research and development will be discussed.
Motoharu Seiki (Division of Cancer Cell Research),
Arinobu Tojo (Division of Molecular Therapy)