Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New strategy rapidly identifies cancer targets

18.07.2006
In a step toward personalized medicine, Howard Hughes Medical Institute investigator Brian J. Druker and colleagues have developed a new technique to identify previously unknown genetic mutations that can trigger cancerous growth. By analyzing the proteins – instead of the genes – inside acute myeloid leukemia (AML) cells, the researchers have dramatically reduced the time it takes to zero in on molecular abnormalities that might be vulnerable to specific drug treatments.

"This approach gives us a way to figure out what's driving the growth of a cancer in an individual patient and ultimately match that patient with the right drug," said Druker, who is based at the Oregon Health & Science University in Portland. Druker's team collaborated on the research, which was published in the July 17, 2006, issue of the journal Cancer Cell, with scientists in the lab of D. Gary Gilliland, an HHMI investigator at Brigham and Women's Hospital, as well as researchers at the Portland VA Medical Center, Cell Signaling Technology, the University of Chicago, and Yale University.

Traditionally, cancer-gene hunters have scanned the genome looking for mutations that trigger out-of-control cell growth. Druker tried this approach, but found it wanting. "We were doing some high-throughput DNA sequencing, and we weren't really finding much," he said.

Instead, the team added tools from the burgeoning field of proteomics, the study of proteins. "We decided this more functional assay would get us to the disease-causing genes more rapidly," said Druker, who has been studying a group of cell-signaling proteins called tyrosine kinases for 20 years.

Tyrosine kinases play a key role in many cancers. In healthy cells, they help form a chain of signals that prompt normal cell growth and division. Sometimes, though, a tyrosine kinase gets stuck in an "on" position, driving out-of-control cell division and, ultimately, cancer. This potentially devastating kinase activation carries a calling card in the form of a molecule called a phosphate.

"The phosphates signal activated tyrosine kinases," said Druker. "So we decided to use the phosphates as markers."

To find these markers, the team took myeloid leukemia cells and chemically digested them into a mixture of protein snippets called peptides. Next, they extracted all of the peptides carrying extra phosphates and sent them through a mass spectrometer, which precisely measured the weight of each peptide. Sophisticated software then sifted through a massive protein database at the National Library of Medicine, identifying each of the team's peptides as a segment of a specific protein. The analysis showed that many of the peptides came from tyrosine kinases. Scanning this list, Druker picked out five as likely suspects.

Druker's team then introduced into their leukemia cells five segments of RNA that each shut down one of the candidate kinases. Silencing four of the kinases with RNA did nothing – the cells still grew out of control. But with the fifth, the cells no longer became cancerous.

"That left one gene to sequence. We found that the gene, called JAK3, had a mutation that drives the growth of leukemia cells in mice," said Druker. Analysis of additional patient samples later identified two more mutations in the JAK3 gene.

Thomas Mercher, a postdoctoral fellow in Gilliland's lab, then tested the mutation in a mouse model. "It was important to show that the JAK3 mutation, when introduced in mice, would lead to a leukemia-like illness. It did, confirming that the JAK3 mutations play a central role in leukemia," said Gilliland.

While Druker said that only a small proportion of AML patients likely carry JAK3 mutations, he says the technique will help find other cancer-causing mutations. The process is highly technical, but it cuts the time needed to find a faulty gene by months. "If you try to sift through DNA, it takes almost a year," said Druker. "This technique takes a couple of months and further automation would make it even quicker."

So quick, in fact, that Druker envisions the technique as a method to help choose which drug a patient's cancer will respond to – a critical step in achieving personalized medicine. Four cancer drugs that inhibit tyrosine kinases are already on the market, including Gleevec, which Druker pioneered for treatment of chronic myelogenous leukemia. Since its approval in 2001, Gleevec has made CML a much more manageable disease.

A new drug to inhibit JAK3 is already in development elsewhere, and, eventually, Druker sees a market filled with a dozen or more tyrosine kinase inhibitors. Matching the patient to the right drug will then simply be a matter of running their cancer cells through a future version of their new technique. Druker is already testing the idea. "Now we know to add JAK3 to the mutations we screen for in our leukemia patients and should look to see if JAK3 mutations are present in other cancers," he said.

Jennifer Michalowski | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Not of Divided Mind
19.01.2017 | Hertie-Institut für klinische Hirnforschung (HIH)

nachricht CRISPR meets single-cell sequencing in new screening method
19.01.2017 | CeMM Forschungszentrum für Molekulare Medizin der Österreichischen Akademie der Wissenschaften

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

New Study Will Help Find the Best Locations for Thermal Power Stations in Iceland

19.01.2017 | Earth Sciences

Not of Divided Mind

19.01.2017 | Life Sciences

Molecule flash mob

19.01.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>