Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Cancer drug might help kids with fatal ’aging’ syndrome


Johns Hopkins scientists have discovered that a drug currently being tested against cancers might help children with a rare, fatal condition called Hutchinson-Gilford progeria syndrome, which causes rapid, premature aging.

Children with progeria appear normal until they’re 6 months to a year old, but then begin developing symptoms normally associated with old age -- wrinkled skin, hair loss, brittle bones and atherosclerosis, which usually causes their deaths by about age 13. There’s no known treatment.

But the new Hopkins research, and similar results from other labs, shows that a class of drugs known as farnesyl transferase inhibitors, or FTIs, can reverse an abnormality in laboratory-grown cells engineered to mimic cells from progeria patients. Such cells have nuclei that aren’t round like normal nuclei but instead have multiple "lobes" and can even look like a cluster of grapes or bubbles.

In the laboratory, however, treating these engineered cells with an FTI already in clinical trials in cancer patients restored the cells to a normal appearance, the researchers report Sept. 26 in the advance online section of the Proceedings of the National Academy of Sciences. The drug blocks the first step in processing the faulty protein that causes the syndrome.

"We’ve been hopeful that our two decades of research on how proteins are processed and modified in cells might ultimately help people with certain forms of cancer," says Susan Michaelis, Ph.D., professor of cell biology at Johns Hopkins’ Institute for Basic Biomedical Sciences.

"But for progeria, we and others only recently learned that it involves the one of the modified proteins we’ve been studying, a nuclear protein called lamin A. As a basic scientist, it is really exciting to have leapfrogged from studying a fundamental process to finding evidence that an existing drug might be useful in treating a devastating disease in children," she says.

Michaelis emphasizes that no one knows whether making the cells’ nuclei look normal will be enough to reverse the disease process or slow it down. "If it does, this will be a wonderful example of how understanding basic biology can lead to new medical treatments," she says.

The class of drugs they tested prevents the first step in cells’ processing of certain critical proteins in yeast and mammals. For more than 20 years, Michaelis has been studying this complex process.

The process starts with a fully assembled protein, then adds a fatty appendage called farnesyl very close to the protein’s end, and then a tiny modification called a methyl group to a nearby building block. Finally, somewhat inexplicably, two proteins known to be modified in this way then undergo an additional step. For these two proteins, and maybe more, the modified end and the adjoining 15 building blocks -- a fraction of the proteins’ original length -- are chopped off by an enzyme discovered in Michaelis’s lab.

In yeast, the protein that gets the full treatment helps the single-celled organisms reproduce -- and the useful protein is the smaller part with all the fancy modifications. In cells’ processing of lamin A in mammals, however, the plain, big chunk is the active part, and it’s critical for the proper function and organization of cells’ nuclei.

In children with progeria, however, a genetic mutation causes a piece of the original lamin A protein to be deleted, a discovery made by National Institutes of Health researchers and reported in 2003. The Hopkins researchers immediately noticed that also missing was the specific point at which the modified end would normally be chopped off -- a biologically crucial event.

"The normal mammalian protein, lamin A, doesn’t have all those modifications; the modified part is thrown away," says Michaelis. "With the disease mutation, however, that fails to occur. Although the failure to make normal lamin A could have wreaked havoc in a number of ways, we hypothesized at the time that the problems in progeria arose specifically because the modifications persist."

So Michaelis and postdoctoral fellow Monica Mallampalli, Ph.D., set out to test that idea. Mallampalli genetically engineered a human cell line (HeLa) to have either of two mutations in the gene for lamin A. One mutation halted the process at the very beginning, by preventing addition of the fatty farnesyl appendage. The other affected the end of the process by preventing cleavage of the otherwise normal, fully modified protein.

"Neither has the correct lamin A protein, but only one has a modified protein hanging around," says Michaelis. "We found that only the cells with the farnesyl-modified protein had the problems seen in cells with the HGPS mutation."

Mallampalli also altered the version of the gene that produces the abnormal, persistently modified, disease-causing protein, called progerin, to uncover the effect of preventing the addition of farnesyl. Sure enough, even though the cells still didn’t have normal lamin A, their nuclei looked normal when the faulty protein couldn’t get modified.

The researchers then obtained an FTI compound made by Michael Gelb and Pravin Bendale at the University of Washington in Seattle to see whether interfering with the enzyme that adds farnesyl would have the same normalizing effect.

"We were thrilled that, as our genetic studies predicted, the experimental drug did the trick," says Michaelis. "Because FTIs are already in advanced clinical trials with cancer patients and seem to be quite well-tolerated, it’s hopeful that they could be tested in patients with progeria fairly quickly."

Cancers are much more common than the progeria syndrome, which only affects about one in 8,000,000 births a year in the United States. Such rare disorders don’t usually attract the attention of drug developers, but the fortunate coincidence that progeria is caused by a protein that requires farnesyl for processing means that existing drugs might help.

FTIs prevent addition of farnesyl to all proteins that have a particular molecular tag. In cancer, the key target among these proteins is one called Ras, which is activated by the same farnesyl-triggered process as lamin A and which promotes cancerous growth when there’s too much of it.

Joanna Downer | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife

nachricht Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Ice shelf vibrations cause unusual waves in Antarctic atmosphere

25.10.2016 | Earth Sciences

Fluorescent holography: Upending the world of biological imaging

25.10.2016 | Power and Electrical Engineering

Etching Microstructures with Lasers

25.10.2016 | Process Engineering

More VideoLinks >>>