Cancer drug might help kids with fatal 'aging' syndrome

<body leftmargin="0" bgcolor="#000060" text="#FFFFFF" link="#FFFF00" vlink="#FF9900"> <table border="0" cellpadding="0" cellspacing="0" width="95%" height="1"> <tr> <center> <td valign="top" width="33%" height="33"> <b> <p class="MsoNormal"><font face="Arial" size="5">Cancer drug might help kids with fatal “aging” syndrome</font></p> </b> <p class="MsoNormal"><font face="Arial" size="1">Sept. 28, 2005<br> Courtesy Johns Hopkins Medical Institutions<br> and World Science staff</font> </p> <p class="MsoNormal"> <b><font size="2" face="Arial">Scientists say there may be new hope for children with a tragic condition that makes them die by their teen years—apparently of old age.</font></b> </p> <p class="MsoNormal"> <b><font size="2" face="Arial">The rare condition, with no known treatment, is called Hutchinson-Gilford progeria syndrome. Children with progeria look normal until they’re around a year old. They then start showing the typical signs of old age—wrinkled skin, hair loss, brittle bones and atherosclerosis, which usually causes their deaths by about age 13. </font></b> </p> <p class="MsoNormal"> <b><font size="2" face="Arial">A drug currently being tested against cancer might help these children, according to scientists with Johns Hopkins School of Medicine in Baltimore, Md.</font></b> </p> <p class="MsoNormal"> <b><font size="2" face="Arial">The researchers said their findings, and similar results from other labs, back up the claim.</font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">A class of drugs known as farnesyl transferase inhibitors, or FTIs, can fix an abnormality in laboratory-grown cells engineered to mimic cells from progeria patients, the researchers said.</font></b> </p> <p class="MsoNormal"> <b><font size="2" face="Arial"> 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. <br> <br> 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 said. </font></b> </p> <p class="MsoNormal"> <b><font size="2" face="Arial">They reported their findings Sept. 26 in the advance online section of the research journal <i>Proceedings of the National Academy of Sciences</i>. </font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">A genetic mutation makes the cells of progeria victims produce a faulty version of a molecule called lamin A. This molecule, a protein, is a component of the membrane that covers the nucleus of cells. Exactly how this results in the syndrome is unclear.</font></b> </p> <p class="MsoNormal"> <b><font size="2" face="Arial">But the drug seems to work, the researchers said, by blocking the first in a sequence of processing steps that the faulty molecule undergoes after it is produced.<br> <br> “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,” said Susan Michaelis, Ph.D., professor of cell biology at the school. <br> <br> “But for progeria, we and others only recently learned that it involves the one of the modified proteins we’ve been studying,” lamin A, she said. </font></b> </p> <p class="MsoNormal"> <b><font size="2" face="Arial">It’s “ 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 said. <br> <br> But no one knows whether making the cells’ nuclei look normal would actually cure or help treat the condition, she said. “If it does, this will be a wonderful example of how understanding basic biology can lead to new medical treatments.”</font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">Cells continually produce a wide variety of molecules, mostly called proteins. These both serve as building blocks of the cells themselves and conduct the activities needed to keep the cells, and the organisms they are part of, alive. </font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">After a protein is first produced, it usually undergoes some additional processing by cellular machinery to shape it into its final form. In progeria patients, it seems something goes wrong with this processing for lamin A. </font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">Normal processing of lamin A, Michaelis said, involves at least two steps. First, a couple of small modifications are made to one end of the molecule. Second, that same end is chopped off and thrown away. </font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">Thus, it might seem the first step is pointless. </font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">In fact, it does seem to be useless in mammals, the researchers said. It may exist, they added, because it’s an evolutionary holdover from much simpler organisms, such as yeast, where it does have a purpose. The yeast actually uses the chopped-off end.</font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">In progeria victims, though, the first step is apparently worse than useless. This is because the second step, the removal, fails to occur. So the alterations made in the first step stay. This was discovered in 2003, Michaelis said.</font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">After the discovery, she said, she conjectured that progeria might somehow be a result of these modifications staying in place. </font></b> </p> <p class="MsoNormal"><font size="2" face="Arial"><b>She and Monica Mallampalli, a postdoctoral fellow at the school, set out to test the idea. Mallampalli genetically engineered human cells to have either of two mutations in the gene that has the code for producing lamin A.</b></font> </p> <p class="MsoNormal"><font size="2" face="Arial"><b> One mutation halted the processing at the very beginning, by preventing the main alteration. The other affected the end of the process, by preventing removal of the of modified bit.</b></font> </p> <p class="MsoNormal"><b><font size="2" face="Arial"> “Neither has the correct lamin A protein, but only one has a modified protein hanging around,” said Michaelis. But only the modified protein had the problems seen in cells with the progeria syndrome mutation, she added. </font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">The modification involves the addition of a fatty appendage called farnesyl to the end of the protein.</font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial"> Mallampalli also experimented with the version of mutant gene that causes the syndrome in actual patients, called progerin. She modified it to again prevent the addition of farnesyl. </font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial"> 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 said.</font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">Finally, the researchers studied whether they could get the same improvements in a simpler way. They decided to try a drug that would disrupt the action of another molecule altogether: the enzyme that adds the farnesyl to the lamin A protein. </font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">This enzyme is called a farnesyl transferase, since it transfers farnesyl. And farnesyl transferase inhibitors are so named because they block the enzyme. </font></b> </p> <p class="MsoNormal"><b><font size="2" face="Arial">It’s believed that they do this by sticking to a protein in the same place where the enzyme would add the farnesyl, snarling the process.<br> <br> Michaelis obtained an FTI compound and tried it. <br> <br> “We were thrilled that, as our genetic studies predicted, the experimental drug did the trick,” said 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.” <br> <br> 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 companies. But the coincidence that progeria is caused by a protein that requires farnesyl for processing means that existing drugs might help, the Hopkins researchers said.<br> <br> </font></b> <b> <font face="Arial" size="2">* * *</font> </p> </b> <p><b><font face="Arial" size="2" color="#FFFFFF">Send us a <a href="mailto:editor@world-science.net">comment</a> on this story, or <a href="mailto:?Body=http://www.world-science.net/othernews/050928_progeriafrm.htm">send it to a friend</a></font></b> </p> <p> </center> </td> </tr> </table> </body>