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Basic research leads to a novel cancer therapy

Cancer researcher Professor Axel Ullrich, a director at the Max Planck Institute of Biochemistry in Martinsried, Germany, already showed at the beginning of the 1990s that blocking blood vessel development in a tumour slows down its growth, and shrinks its tissue. This fundamental principle led to the development of SUTENT®, whose active ingredient is Sunitinib. SUTENT® was recently approved for clinical use in the United States, and it is expected to be brought onto the German market this year.

When particular growth factors are bound to specific receptors on the surface of a cell, this can cause the cell to propagate itself and build certain tissue similar to blood vessels. Worldwide, research into receptors has focused on a special class of proteins, called tyrosine kinases. They are responsible for causing the received signal to be transduced through a long signalling cascade into the nucleus, triggering cell division and multiplication. Signalling cascades are absolutely necessary, if various tissues - like blood vessels, nerve tissue, and connective tissue - are to be built up during the development of an organism and in the process of tissue regeneration.

Research has focussed on these tumour cell signalling cascades, because in cancers they are often disturbed. If there were a way to block growth factors, or the receptors on the cellular surface from tumour cells, that could lead to targeted therapies against cancers. Already in the 1980s, cancer researcher Axel Ullrich, then a scientist at Genentech (USA), working with colleagues in the UK and Israel, succeeded in describing the structure and function of a receptor for epidermal growth factor (EGF). Since then, tyrosine kinases and various growth factors have been at the focus of research and development of therapies against tumours.

Also, over a decade ago, a team led by Ullrich discovered that by interrupting the oxygen and nutrient supply to tumour cells, it is possible to inhibit cancer development. The Max Planck scientists showed that tumour tissue just a few cubic millimetres in size can create vascular endothelial growth factor (VEGF), which triggers blood vessel development.

Ullrich found some of the most important evidence in research on animals, conducted with colleagues Birgit Millauer and the late Werner Risau, formerly of the Max Planck Institute of Neurobiology. There is a receptor specific to VEGF, called Flk-1/VEGFR2, found only in endothelial cells which are the building stones of new blood vessels. When Flk-1/VEGFR2 is made inoperative, this blocks the development of tumours. If no blood vessels are created in tumour tissue, the tumour fails to grow. This discovery led to the invention of what are called angiogenesis inhibitors (angiogenesis is the process of blood vessel formation).

Ullrich and the Max Planck Society, in co-operation with New York University, founded SUGEN, Inc. in California in 1991. SUGEN is the first biotechnology company with roots in the Max Planck Society. The firm developed chemical substances which block Flk-1/VEGFR2 in endothelial cells. At the end of the 1990s SUGEN was taken over by Pharmacia, which itself was bought by Pfizer in 2003. Development of the project continued at Pfizer. SUTENT® (active ingredient Sunitinib) has now reached the market as a multi-targeted tyrosine kinase inhibitor, which blocks both the building of blood vessels in tumours as well as other illness-related enzymes in tumour cell signalling networks.

Clinical studies with GIST patients looked into their ability to tolerate Sunitinib, as well as its effectiveness on them. Some of these patients had already been treated with Imatinib, but their tumours continued to develop. Others were not able to tolerate Imatinib at all. Still other patients had advanced renal cell carcinoma with failed available treatment. In the case of the GIST patients, it took four times longer for tumours to renew growth when treated with Sunitinib, compared to the placebo group. Patients with advanced renal cell carcinoma saw a shrinking of the tumour; in 26 to 37 percent of them, the tumour shrunk to at least half its size.

Sunitinib has not yet been approved in Germany, but approval and market entry are expected in this year. Sunitinib is administered after diagnosis. A large number of further clinical studies has shown that Sunitinib has multiple effects on tumour cells and can thus be defined as a novel "multi-targeted" drug.

Sunitinib is being tested now, as well, on patients with advanced forms of bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck tumours, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, and testicular cancer. The studies are in various stages of clinical trials (phases I through III), and most of them are being carried out in combination with other therapies.

Ullrich is very pleased with the quick approval of SUTENT®. He says, "Already before approval, 1,700 patients could be treated with the new preparation, thanks to the Accelerated Approval Process. Naturally, we're happy that our research led so quickly to application in cancer therapy. Each year, 390,000 people in Germany alone, and several million worldwide, become ill with cancer. Every fourth death is related to a tumour. We can improve the length and quality of patients' lives by treating them with very specific drugs, which attack a variety of characteristics of tumour cells. Therapy with multi-targeted substances which block signal transduction in tumour cells is a new breakthrough in the war on cancer. They attack critical cancer cell functions in multiple ways and are well tolerated by patients."

This is the second time that Ullrich has played a leading role in the development of a successful cancer therapy. Seven years ago, his research led the breast-cancer therapy Herceptin® to be br ought to the market by Genentech. In contrast to SUTENT®, Herceptin® attacks the efforts of genetic alterations in the cells of certain forms of breast and ovarian cancer. It blocks the receptor Her2/neu in these cells, which thereby stop growing and become more specific to the immune system.

Since then, Ullrich and his colleagues have applied for some 60 patents - this makes him one of the most successful cancer researchers in the world. He has founded four biotechnology companies, three of them on the campus in Martinsried. Since 1988 he has led the Department of Molecular Biology at the Max Planck Institute of Biochemistry. Last year he established the "OncoGenome Project" in Singapore's Centre for Molecular Medicine, a member of the Agency for Science, Technology, and Research (A*STAR).



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