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 Laser activated gold pyramids could deliver drugs, DNA into cells without harm
24.03.2017 | Harvard John A. Paulson School of Engineering and Applied Sciences

nachricht What does congenital Zika syndrome look like?
24.03.2017 | University of California - San Diego

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: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>