Axel Ullrich, 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 ( Sunitinib ).

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.

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.

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 ( 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 ( Gleevec/Glevec ), 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 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.

Source: Max-Planck-Gesellschaft, 2006


XagenaMedicine2006