Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

'Synthetic lethality' strategy improves molecularly targeted cancer therapy

22.09.2010
Molecularly targeted therapies can reduce tumors rapidly. However, not all tumors respond to the drugs, and even those that do often develop resistance over time. Looking for a way to combat the problem of resistance, researchers at Fox Chase Cancer Center hypothesized that hitting already weakened cancer cells with a second targeted agent could kill them—but only if it was the right second agent.

One well-validated molecular target for anti-cancer drugs is the epidermal growth factor receptor, or EGFR. Using a novel screening approach, investigators in the Fox Chase Developmental Therapeutics Program identified over 60 additional proteins that are necessary for cells to survive in the presence of an EGFR inhibitor.

When they simultaneously blocked the EGFR inhibitors and any one of these other proteins, more of the cancer cells died. The researchers say this screening strategy to identify targets for effective combinations of cancer drugs will open the door for future therapies. Already, two clinical trials are under way to test innovative drug combinations suggested by the new tactic.

"We found that knocking out one or the other target doesn't have a major effect, but knocking out both increases tumor cell death," says Igor Astsaturov, M.D., Ph.D., an assistant professor and medical oncologist at Fox Chase. Astsaturov led the study, which will be published in the September 21, 2010 issue of Science Signaling.

To identify additional targets that would boost the effectiveness of EGFR inhibitors against cancer, Astsaturov and colleagues screened only proteins that interact directly or indirectly with EGFR. The team mined the literature and built a candidate set of 638 EGFR-interacting proteins. They then used an experimental technique called small inhibitory RNA (siRNA) systematically to block activity of each of the genes in cancer cells that had been treated with an EGFR inhibitor. In doing so, the investigators demonstrated on three clinically relevant examples for which drugs are already available—PRKC, STAT3, and Aurora kinase A—that these proteins were necessary for cell survival in the presence of an EGFR inhibitor.

This two-hit strategy—where neither hit is adequate to kill the cells, but together they are—is called synthetic lethality. Geneticists have used synthetic lethal screens in experiments with model organisms, such as fruit flies and yeast, for decades, but cancer researchers have only recently adopted the approach.

"We knew from model organisms that there was a dense network of genes. Using bioinformatics tools to intelligently mine this network provided us with a rich source of hits," says Erica A Golemis, Ph.D., professor and co-leader of the Developmental Therapeutics Program at Fox Chase, and senior author on the new study. Golemis is also co-leader of the Keystone Initiative in Head and Neck Cancer at Fox Chase, and notes that EGFR inhibitors are already broadly used in the clinic for cancers affecting the head and neck.

"The most exciting hit is the Aurora kinase," Golemis says. Several Aurora kinase inhibitors are already being tested in the clinic and thus are available for testing in combination with EGFR inhibitors.

Based on the new data, Hossein Borghaei, D.O., director of the Lung Cancer Risk Assessment Program at Fox Chase is launching a trial testing the EGFR inhibitor erlotinib with an Aurora kinase inhibitor in patients with non-small cell lung cancer. Astsaturov has started testing a drug called vandetanib—which simultaneously inhibits EGFR and RET (another protein in the EGFR-interacting network)—in patients with esophageal cancer.

In addition to providing a rich source of synthetic lethal hits, limiting the siRNA screen to a previously-defined network of interacting proteins had an important impact on the size of the project, according to Golemis. "A full genome siRNA screen is prohibitively expensive for many labs. This approach makes siRNA screens more accessible to smaller labs and academic institutions."

Louis M. Weiner of Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, is co-principal investigator on the study, and continues to collaborate with the Fox Chase team to extend this work.

Fox Chase Cancer Center is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation's first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center's nursing program has received the Magnet status for excellence three consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. For more information, visit Fox Chase's Web site at www.fccc.org or call 1-888-FOX CHASE or (1-888-369-2427).

Diana Quattrone | EurekAlert!
Further information:
http://www.fccc.edu

More articles from Health and Medicine:

nachricht Neutrons produce first direct 3D maps of water during cell membrane fusion
21.09.2018 | DOE/Oak Ridge National Laboratory

nachricht Narcolepsy, scientists unmask the culprit of an enigmatic disease
20.09.2018 | Universitätsspital Bern

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Scientists present new observations to understand the phase transition in quantum chromodynamics

The building blocks of matter in our universe were formed in the first 10 microseconds of its existence, according to the currently accepted scientific picture. After the Big Bang about 13.7 billion years ago, matter consisted mainly of quarks and gluons, two types of elementary particles whose interactions are governed by quantum chromodynamics (QCD), the theory of strong interaction. In the early universe, these particles moved (nearly) freely in a quark-gluon plasma.

This is a joint press release of University Muenster and Heidelberg as well as the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt.

Then, in a phase transition, they combined and formed hadrons, among them the building blocks of atomic nuclei, protons and neutrons. In the current issue of...

Im Focus: Patented nanostructure for solar cells: Rough optics, smooth surface

Thin-film solar cells made of crystalline silicon are inexpensive and achieve efficiencies of a good 14 percent. However, they could do even better if their shiny surfaces reflected less light. A team led by Prof. Christiane Becker from the Helmholtz-Zentrum Berlin (HZB) has now patented a sophisticated new solution to this problem.

"It is not enough simply to bring more light into the cell," says Christiane Becker. Such surface structures can even ultimately reduce the efficiency by...

Im Focus: New soft coral species discovered in Panama

A study in the journal Bulletin of Marine Science describes a new, blood-red species of octocoral found in Panama. The species in the genus Thesea was discovered in the threatened low-light reef environment on Hannibal Bank, 60 kilometers off mainland Pacific Panama, by researchers at the Smithsonian Tropical Research Institute in Panama (STRI) and the Centro de Investigación en Ciencias del Mar y Limnología (CIMAR) at the University of Costa Rica.

Scientists established the new species, Thesea dalioi, by comparing its physical traits, such as branch thickness and the bright red colony color, with the...

Im Focus: New devices based on rust could reduce excess heat in computers

Physicists explore long-distance information transmission in antiferromagnetic iron oxide

Scientists have succeeded in observing the first long-distance transfer of information in a magnetic group of materials known as antiferromagnets.

Im Focus: Finding Nemo's genes

An international team of researchers has mapped Nemo's genome

An international team of researchers has mapped Nemo's genome, providing the research community with an invaluable resource to decode the response of fish to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

"Boston calling": TU Berlin and the Weizenbaum Institute organize a conference in USA

21.09.2018 | Event News

One of the world’s most prominent strategic forums for global health held in Berlin in October 2018

03.09.2018 | Event News

4th Intelligent Materials - European Symposium on Intelligent Materials

27.08.2018 | Event News

 
Latest News

Astrophysicists measure precise rotation pattern of sun-like stars for the first time

21.09.2018 | Physics and Astronomy

Brought to light – chromobodies reveal changes in endogenous protein concentration in living cells

21.09.2018 | Life Sciences

"Boston calling": TU Berlin and the Weizenbaum Institute organize a conference in USA

21.09.2018 | Event News

VideoLinks
Science & Research
Overview of more VideoLinks >>>