Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study raises safety concerns about experimental cancer approach

26.01.2011
Widespread vascular tumors, massive hemorrhage and death reported in mice

A study by researchers at Washington University School of Medicine in St. Louis has raised safety concerns about an investigational approach to treating cancer.

The strategy takes aim at a key signaling pathway, called Notch, involved in forming new blood vessels that feed tumor growth. When researchers targeted the Notch1 signaling pathway in mice, the animals developed vascular tumors, primarily in the liver, which led to massive hemorrhages that caused their death.

Their findings are reported online Jan. 25 in The Journal of Clinical Investigation and will appear in the journal’s February issue.

A number of anti-Notch therapies now are being evaluated in preclinical and early clinical trials for cancer. They target Notch1 as well as the three other signaling pathways in the Notch receptor family. The current research did not study any of these specific therapies in mice but instead focused on the potential side effects of chronically disrupting the Notch1 signal in individual cells.

“Our results suggest that anti-Notch1 strategies are bound to fail,” says Raphael Kopan, PhD, professor of developmental biology and of medicine at the School of Medicine. “Without the Notch1 signal, cells in the vascular system grow uncontrollably and produce enlarged, weakened blood vessels. Eventually, the pressure within those vessels exceeds their capacity to hold blood, and they rupture, causing a dramatic loss of blood pressure, heart attack and death.”

Notch plays a crucial role in determining a cell’s fate and is active throughout a person’s life. In recent years, the pathway has emerged as a target to block the formation of blood vessels – called angiogenesis – in solid tumors.

Kopan says he is not advising that anti-Notch clinical trials already under way be halted. These early trials generally involve short-term use of the drugs and are designed to assess safety. However, he says patients who take anti-Notch therapies for extended periods should receive MRI scans to check for liver abnormalities.

In the new research, Kopan and his colleagues engineered mice to develop random but progressive disruptions in the Notch1 gene in cells that depend on its signal. This model mimics a scenario that may occur in cancer patients receiving anti-Notch therapies for extended time periods.

Then, the researchers monitored the mice for any potential negative consequences and compared the outcomes of 41 mutant mice to 45 normal “control” mice.

Within several months, the experimental mice developed opaque corneas, which were already known to be associated with a loss of Notch1 signaling.

Otherwise, for more than a year, the genetically engineered mice appeared to grow and develop normally. Then, for no apparent reason, they started dying suddenly.

The researchers conducted autopsies on 13 pairs of experimental and control mice. They noted vascular tumors and/or abnormal collections of blood vessels called hemangiomas in 85 percent (11/13) of the mutant mice, primarily in the liver. Some of the mice developed additional tumors in the uterus, colon, lymph nodes, skin, ovary and testis.

None of the control animals developed vascular tumors or hemangiomas. On average, the experimental mice lived 420 days compared with 600 days for the control mice.

“It is highly unlikely that mice in the experimental group would randomly die so soon,” Kopan explains. “When we examined the mice, we found evidence of ruptured blood vessels and pooling of blood in their body cavities along with an odd-looking liver pathology.”

The investigators then conducted MRI scans on living experimental mice. They noted that their livers had holes that looked “like a big Swiss cheese instead of having a dense, reddish, featureless landscape,” Kopan says. “This is highly abnormal.”

All the evidence pointed to abnormalities in the endothelial system in the experimental mice. Endothelial cells line blood vessels, allowing them to expand and contract as blood is pumped through the body. For reasons the researchers don’t yet understand, endothelial cells in the liver were most affected. Ninety percent of the proliferating liver endothelial cells in the experimental mice had lost the Notch1 signal.

Notch plays many roles in the body, depending on the cellular context. In some instances, Notch can spur tumor growth and in others suppress it. The researchers suspect that loss of the Notch1 signal in the experimental mice releases the brakes on endothelial cell division, allowing the cells to proliferate uncontrollably, particularly in the liver.

Anti-notch compounds now in preclinical and clinical trials include gamma secretase inhibitors, originally developed to treat Alzheimer’s disease. These drugs block an enzyme all Notch receptors rely on. Other drugs in the pipeline are called DLL4 antibodies, which also disrupt Notch signaling and blood vessel formation. Anti-Notch1 antibodies are also being developed.

Kopan, however, says he is not optimistic about the prospects for any of them.

“The therapeutic window for any kind of anti-Notch1 therapy – that’s the dosage of a drug that is both safe and effective – is extremely small, perhaps even nonexistent, for these compounds in their current form," he says. "We need to do additional research to try to find out how we can open that window."

The research was funded by the National Institutes of Health, the National Cancer Institute and the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.

Liu Z, Turkoz A, Jackson EN, Corbo JC, Engelbach JA, Garbow JR, Piwnica-Worms DR, Kopan R. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. The Journal of Clinical Investigation. February 2011.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Caroline Arbanas | EurekAlert!
Further information:
http://www.wustl.edu
http://news.wustl.edu/news/Pages/21788.aspx

More articles from Studies and Analyses:

nachricht The Great Unknown: Risk-Taking Behavior in Adolescents
19.01.2017 | Max-Planck-Institut für Bildungsforschung

nachricht A sudden drop in outdoor temperature increases the risk of respiratory infections
11.01.2017 | University of Gothenburg

All articles from Studies and Analyses >>>

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

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>