[ZucchiniFlower]

Read this on the train this morning and it made me smile. This seems so simple, and direct. Maybe one day for PD, too....

Reactivated gene shrinks tumors, MIT study finds

Anne Trafton, News Office
January 24, 2007

Many cancers arise due to defects in genes that normally suppress tumor growth. Now, for the first time, MIT researchers have shown that re-activating one of those genes in mice can cause tumors to shrink or disappear.

The study offers evidence that the tumor suppressor gene p53 is a promising target for human cancer drugs.

"If we can find drugs that restore p53 function in human tumors in which this pathway is blocked, they may be effective cancer treatments," said David Kirsch of MIT's Center for Cancer Research and Harvard Medical School, one of the lead co-authors of the paper.

The study is published in the Jan. 24 online edition of Nature. It was conducted in the laboratory of Tyler Jacks, director of the Center for Cancer Research, the David H. Koch Professor of Biology and a Howard Hughes Medical Institute investigator.

P53 has long been known to play a critical role in the development of many tumors--it is mutated in more than 50 percent of human cancers. Researchers have identified a few compounds that restore p53 function, but until now, it has not been known whether such activity would actually reverse tumor growth in primary tumors.

The new MIT study shows that re-activating p53 in mouse tumors dramatically reduces the size of the tumors, in some cases by 100 percent.

"This study provides critical genetic evidence that continuous repression of a tumor suppressor gene is required for a tumor to survive," said Andrea Ventura, an Italian postdoctoral associate in the Center for Cancer Research and first author of the paper.

In normal cells, p53 controls the cell cycle. In other words, when functioning properly, it activates DNA repair mechanisms and prevents cells with damaged DNA from dividing. If DNA damage is irreparable, p53 induces the cell to destroy itself by undergoing apoptosis, or programmed cell death.

When p53 is turned off by mutation or deletion, cells are much more likely to become cancerous, because they will divide uncontrollably even when DNA is damaged.

In this study, the researchers used engineered mice that had the gene for p53 turned off. But, they also included a genetic "switch" that allowed the researchers to turn p53 back on after tumors developed.

Once the switch was activated, p53 appeared in the tumor cells and the majority of the tumors shrank between 40 and 100 percent.

The researchers looked at two different types of cancer--lymphomas and sarcomas. In lymphomas, or cancers of the white blood cells, the cancer cells underwent apoptosis within 1 or 2 days of the p53 reactivation.

In contrast, sarcomas (which affect connective tissues) did not undergo apoptosis but went into a state of senescence, or no growth. Those tumors took longer to shrink but the senescent tumor cells were eventually cleared away.

The researchers are not sure why these two cancers are affected in different ways, but they have started trying to figure it out by identifying the other genes that are activated in each type of tumor when p53 turns back on.

The study also revealed that turning on p53 has no damaging effects in normal cells. The researchers had worried that p53 would kill normal cells because it had never been expressed in those cells.

"This means you can design drugs that restore p53 and you don't have to worry too much about toxic side effects," said Ventura.

Possible therapeutic approaches to turn on p53 in human cancer cells include small molecules that restore mutated p53 proteins to a functional state, as well as gene therapy techniques that introduce a new copy of the p53 gene into tumor cells. One class of potential drugs now under investigation, known as nutlins, acts by interfering with MDM2, an enzyme that keeps p53 levels low.

In follow-up studies, the MIT researchers are looking at other types of cancer, such as epithelial (skin) cancer, in their mouse model, and they plan to see if the same approach will also work for tumor suppressors other than p53.

This research was funded by the Howard Hughes Medical Institute, the National Cancer Institute, the American Italian Cancer Research Foundation and the Leaf Fund.

Other authors on the paper are Margaret McLaughlin, a former postdoc in Jacks' lab, now at Novartis; David Tuveson, also a former postdoc, now group leader at the Cambridge Research Institute (United Kingdom); Laura Lintault, a research affiliate in the Center for Cancer Research; Jamie Newman, graduate student in MIT's Department of Biology; Elizabeth Reczek, a former graduate student in Jacks' lab, now a postdoctoral fellow at Brigham and Women's Hospital; Ralph Weissleder, a professor of radiology at Harvard Medical School and director of the Center for Molecular Imaging Research; and Jan Grimm, a former postdoc in Weissleder's lab, now at Memorial Sloan Kettering Cancer Center.

A version of this article appeared in MIT Tech Talk on February 7, 2007

[ZucchiniFlower]

Clinic part of trial of very promising' Parkinson's treatment
Sunday, February 25, 2007
Zachary Lewis
Plain Dealer Reporter

Researchers at the Cleveland Clinic are collaborating with eight medical institutions nationwide to test what they call a promising new treatment for Parkinson's disease.

"This would be a whole new paradigm," said Nicholas Boulis, a Clinic neurosurgeon and the primary investigator in the local trial. "It's really opening up a whole new way of approaching Parkinson's."

Under examination is CERE-120, a manufactured gene transfer agent that prompts the brain to repair itself.

Specifically, CERE-120 is an adeno-associated virus carrying a gene that causes the brain to produce neurturin, a naturally occurring protein that repairs damaged dopamine neurons.

Dopamine loss leads to the involuntary movements symptomatic of Parkinson's. Thus, CERE-120 stands to halt or even reverse the effects of the disease.

"I think this is very promising," said Marilyn Brandt, president of the Parkinson's Education Program of Greater Cleveland, a local support group.

Nearly 50,000 Americans have Parkinson's disease diagnosed every year. The disease affects 4.3 million worldwide.

A unique feature of the CERE-120 trial is the method of delivery. Existing dopamine treatments such as patches distribute substances across the brain, but CERE-120 is administered through precise injection into the putamen, part of the brain that influences movement.

The surgery consists of drilling two holes in the skull and, navigating by magnetic resonance imaging, delivering eight CERE-120 injections.

"Basically, the putamen evaluates everything you're trying to do from a motor perspective and decides whether or not to let it happen," Boulis said. "To be effective, treatments need to be in the exact right part, and they need to be there a long time."

Results so far have been encouraging. Twelve patients who received the surgery in Phase I trials at the University of California-San Francisco and Rush University Medical Center in Chicago reported a 40 percent improvement in their motor skills.

Side effects included mild to moderate temporary dyskinesia, or involuntary movement. This was treated successfully by readjusting the dosage of traditional Parkinson's medications, Boulis said.

Another advantage of CERE-120: "You don't have a wire and battery in your body," Boulis said, referring to equipment left over from deep-brain stimulation, another Parkinson's treatment.

Fifty-one participants nationwide are being sought for the trial's second phase, and enrollment is still open. Seventeen patients will be part of a control group and not receive CERE-120 initially.

In addition to the work in Cleveland, San Francisco and Chicago, trials are taking place in Birmingham, Ala.; New York; Durham, N.C.; Portland, Ore.; Houston; and Philadelphia.

"We've got to try every avenue there is, and we've got to try them on people," Brandt said. "Everybody's hoping one of them will break through."

To be eligible for the trial, participants must be 35 to 75 years old, have had the disease for five years and have pursued dissimilar treatments without success. Exclusionary factors include atypical forms of the disease, chemotherapy, history of drug or alcohol abuse and the presence of medical conditions that could complicate surgery.

The Michael J. Fox Foundation says it has contributed more than $2.6 million in support of the trials.

****Thanks, Michael!