25 September 2014

A mousetrap for metastases

A promising alternative to cancer chemotherapy

Nanonewsnet based on Stanford University materials:
Stanford researchers create 'evolved' protein that may stop cancer from spreadingTo block one of the molecular cellular signaling pathways – the trigger for the separation of cancer cells – in other words, to suppress the signal that initiates metastasis, scientists have created a decoy protein.

Preliminary tests have shown the effectiveness of this strategy in mouse cancer models; the introduction of a bioengineered protein significantly suppresses metastasis in mice with aggressive breast and ovarian cancer. There are years of trials ahead, but this is a promising start to an alternative chemotherapy treatment method.

A group of scientists from Stanford University has developed a protein that blocks the process necessary for a cancer cell to break away from the primary tumor, begin its journey through the circulatory system and give rise to aggressive neoplasms in other parts of the body. This process, known as metastasis, allows cancer to spread and often portends a fatal outcome of the disease.

"Most cancer patients fall victim to metastatic forms of this disease," says associate professor of bioengineering Jennifer Cochran, senior author of an article on a new therapeutic approach published in the journal Nature Chemical Biology (Kariolis et al., An engineered Axl "decoy receptor" effectively silences the Gas6-Axl signaling axis).

Today, doctors are trying to slow down or stop metastasis with chemotherapy, but unfortunately, chemotherapy drugs are not effective enough and have serious side effects.

Stanford scientists aim to stop metastasis without side effects by blocking the interaction of two proteins – Axl and Gas6.

Axl protein molecules are located on the surface of cancer cells and are ready to receive biochemical signals from Gas6 molecules.

The formation of a bond between two Gas6 molecules and two Axls molecules is a signal that gives cancer cells the opportunity to leave the primary tumor, migrate to other parts of the body and form new cancer nodes.

To stop this process, Dr. Cochran created a harmless variant of Axl – a product of protein engineering – acting as a bait for Gas6. This variant of Axl interacts with Gas6 in the blood, thereby preventing its interaction with Axl molecules on the surface of cancer cells and activation of this protein.

In collaboration with Professor Amato Giaccia, who heads the Radiation Biology Program at Stanford University Cancer Center, researchers tested this bioengineered protein bait on mice with aggressive breast and ovarian cancer.

Intravenous administration of engineering protein dramatically reduced the number of metastases in experimental animals. In mice with breast cancer, the number of metastatic nodes was 78 percent less than in control animals. In the group of mice with ovarian cancer, this figure was 90 percent.

"This is a very promising method of therapy, which in preclinical experiments shows itself to be effective and non–toxic," says Professor Jakcha. "It could open the way to a new approach to cancer treatment."

Greg Lemke from the Laboratory of Molecular Neurobiology at the Salk Institute for Biological Studies called the results of this study "a vivid example of the possibilities of bioengineering" in the development of new therapeutic approaches to the treatment of metastatic cancer.

"The affinity of the bait protein is particularly remarkable in this work," says Lemke, a recognized authority on Axl and Gas6 proteins who did not participate in the Stanford experiments. "The binding efficiency of the bait protein with Gas6 is up to a hundred times higher than that of the natural Axl protein. It just absorbs Gas6 and puts it out of action."

The approach of Stanford scientists is based on the fact that all biological processes are triggered by the interaction of proteins – molecules that spatially correspond to each other according to the principle of key and lock. It is this correspondence that allows them to perform all the functions necessary for the life of biological objects.

In nature, proteins evolve over millions of years. But bioengineers have developed ways to speed up the process of improving these tiny molecules using a technology called directed evolution.

With the help of genetic manipulation, Dr. Cochran and her group created millions of slightly different DNA sequences. Each of these sequences encoded distinct Axl variants.

Then, after evaluating over 10 million Axl variants using high-performance screening, the researchers found the variant that most strongly binds to Gas6.

To make a conclusion about the safety and effectiveness of using this method in clinical practice, more years of work are needed: first, bioengineers must establish the production of sufficient quantities of Axl and obtain pure material for testing, and then clinical scientists must conduct preclinical and animal tests. These are expensive and time-consuming steps.

But the first results give hope that a non-toxic method of combating metastatic cancer can be developed based on the Stanford approach.

Glenn Dranoff, Professor of Medicine at Harvard Medical School, a leading researcher at the Dana-Farber Cancer Institute, is the author of a review of an article by Stanford scientists. In no other way connected with their work, he commented about this study: "It's a beautiful biochemistry, and there are some nuances in it that make it especially interesting."

Tumors often use more than one way to ensure their survival and spread. Axl has two relatives, Mer and Tyro3, which are also able to stimulate metastasis. Both Mer and Tyro3 are also activated by the Gas6 protein.

"Thus, one therapeutic bait can potentially have an effect on all three related proteins that play a crucial role in the development and progression of cancer," explains Professor Dranoff.

Professor Jakcha and Dr. Cochran are scientific consultants of Ruga Corp, a biotech startup in Palo Alto, which has received a license for this technology from Stanford University.

Portal "Eternal youth" http://vechnayamolodost.ru25.09.2014

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