Basic research at the Max Planck Institute of Biochemistry leads to a novel cancer therapy

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Basic research at the Max Planck Institute of Biochemistry leads to a

novel cancer therapy

Axel Ullrich, at the Max Planck Institute of Biochemistry in

sried, 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