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September 26, 2007

Inaugural Taubman Institute Scholars

Valerie Castle: Improving treatments for neuroblastoma
Taubman gift will fund research into deadly childhood cancer

Valerie Castle
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While cancer research has led to many exciting discoveries and improved survival rates, certain cancer types are proving to be more difficult problems to solve.

Neuroblastoma, which strikes about 650 children each year, is one. Even after extensive treatment, fewer than 15 percent of children with advanced neuroblastoma survive.

The Taubman Institute funding will allow Valerie Castle, M.D., chair of the Department of Pediatrics and the Ravitz Foundation Professor of Pediatrics and Communicable Diseases at the University of Michigan Health System, to expand research into this devastating childhood cancer.

“This funding will really allow us to expand upon the studies we’ve started that are in preliminary stages but show great promise to advance ideas on new treatment strategies very, very rapidly. When we’re given the latitude to make research investments in the most innovative ideas we have, it is an extraordinary opportunity,” Castle says.

Castle and her team are exploring the pathways that lead to neuroblastoma. By zeroing in on these pathways, they have identified molecules that cause the cancer to form and that make it resistant to current chemotherapies and radiation therapy. They hope to now find ways to pirate these molecules, turning them into weapons that will actually kill the cancerous cells.

“Our focus is to understand the disease and how it develops in young children, so that we can block its ability to be so aggressive and find define more effective treatment strategies,” Castle says.

Castle’s research may also have implications beyond neuroblastoma. Basic discoveries in rare cancers often lead to new advances in other cancer areas.

In fact, Castle notes, some of the pathways her team is studying have implications for breast cancer and ovarian cancer.

“This funding is extraordinary,” Castle says of the Taubman gift. “It’s going to allow us to embark on some very unique and innovative experiments in the lab that will accomplish a series of scientific objects that are designed around the single purpose of moving these ideas toward new treatments. Often, innovative approaches are not well-funded at an early critical stage, making it difficult to take on projects that, albeit with some risk, have very high up-side potential.”

Ultimately, she says, “Our goal is to have Mr. Taubman’s investment in this research turn into new clinical trials that will be available at Michigan and elsewhere for children with neuroblastoma.”

Eva Feldman: Testing stem cells to treat Lou Gehrig’s disease

Work aims to counter the devastation of amyotrophic lateral sclerosis (ALS)

Eva Feldman
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Of all the human diseases, it’s hard to think of one crueler than amyotrophic lateral sclerosis, or ALS – sometimes known as Lou Gehrig’s disease for one of its most famous victims.

The condition strikes during the prime of life, and causes steady degradation of the nerves that control muscle movement. This process continues, unstoppable, for years until the body is completely devastated – even while the mind is alert and functioning. The cause is unknown, except for gene mutations responsible for a small minority of cases. There is no cure, and while treatments have improved somewhat in recent years, the diagnosis is a death sentence.

Eva Feldman, M.D., Ph.D., treats patients with this disease every week, as director of the U-M’s ALS Clinic and the DeJong Professor of Neurology at the U-M Medical School. She brings the weight of her patients’ stories with her back to the laboratory, the Program for Neurology Research and Discovery, where she leads a team of scientists who are trying to understand why ALS happens, and how new treatments can get on the fast track to help patients today and in the future. 

Already, the team is using genetically engineered rats that carry the mutated gene, called SOD1, that causes ALS in the 10 percent of human patients who inherit a familial form from their parents. This rat model of ALS serves as an important tool for understanding ALS and for testing new treatments. Part of this work has been supported by $7 million in gifts that Mr. Taubman has given directly to the Feldman lab’s ALS research, spurred by the memory of a dear friend that he lost to the disease.

Now, the Taubman Institute funding will allow the team to test a specific ALS treatment: stem cells.

Together with collaborator Martin Marsala, M.D., of the University of California, San Diego School of Medicine, and using human nervous-system stem cells from a company called NeuralStem, the team will study whether injections of stem cells into the spinal cord may be an effective treatment to counteract the destruction of nerve cells in ALS. If the tests are successful, clinical trials may begin within five years.

“This is work that we could not do without the Taubman funding,” Feldman says. “It’s very discovery-driven – we do not know if it is or isn’t going to work.”

The current scientific funding climate, in which the National Institutes of Health must prioritize the spending of its flat budget to support hypothesis-driven research rather than discovery-driven science, makes this type of support all the more important, she says. “Without discovery science, without trying to break forward and push the barriers, we can’t make the truly meaningful discoveries. Mr. Taubman is funding discovery science, and it’s from discovery science that we’ll make real breakthroughs. High risk brings high reward in medicine and science. ”

As someone who has known Mr. Taubman for years, Feldman says she knows what motivated his gift – beyond his love of the University of Michigan.

“He is intellectually curious. and he truly wants to understand what causes disease. He’s a very compassionate and passionate person,” she says. “He is very committed to helping us transform the world of medical research. He’s willing to put in large dollars, realizing that it’s high risk, but that there are the high rewards that our university will reap, society as a whole will reap, and in many ways, people that he knows and has been touched by will reap.”

David Pinsky: Seeking a low-risk solution to unwanted clots

Blood-vessel cell enzymes may yield better treatment for heart attack & stroke

David Pinsky
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Heart attacks and most strokes have a lot in common. Both are medical emergencies caused by tiny blood clots that break off from the lining of a blood vessel, and get stuck inside smaller vessels, blocking the flow of blood in the area and leading to the death of heart muscle or brain tissue.

For decades, medical science has tried to figure out how to minimize that damage by quickly restoring that blood flow -- without causing too much bleeding. A perfect solution remains elusive. 

David Pinsky, M.D., and his laboratory team believe they’re on track to find a better way to accomplish this goal. Their strategy is based on a type of protein that protrudes from the surface of the cells that line every blood vessel in the body. These cells, called endothelial cells, are the traffic cops of the circulatory system, ensuring smooth flow of blood to our tissues and organs -- and calling for backup from the immune system during emergencies such as cuts, infections and clots.

Dr. Pinsky's team studies mice with atherosclerosis (clogged arteries) and stroke, to better understand the human forms of these diseases. These images show the brain and the aorta (largest blood vessel in the body) of mice from their studies. The red areas, which show the location where a stroke began in the mouse brain, and where plaque has built up in the mouse aorta, are stained with a special stain that attaches to lipids, or fats.

 

The proteins on the surface of these cells are called ectoenzymes, and it is these enzymes that Pinsky and his team will study with their Taubman Institute funding. Specifically, they have zeroed in on a single ectoenzyme that can stop the formation of a clot by interfering with the signals that blood platelets send out during the very early stages of clot formation.

“We’re far from a therapy but we certainly have dreams,” says Pinsky, who is one of four directors of the U-M Cardiovascular Center, and chief of the Division of Cardiovascular Medicine in the Department of Internal Medicine, as well as the J. Griswold Ruth M.D. & Margery Hopkins Ruth professor in internal medicine and a professor in the Department of Molecular & Integrative Physiology. “What we could conceivably do is take that enzyme, and make it, or a portion of it, to be given in an urgent setting to abort clot formation.”

The research needed to find out whether this is possible has already begun, and in fact the Pinsky laboratory team has already used a genetically engineered “clipped” version of the enzyme, and shown in animals that it can be effective in restoring blood flow after a stroke. Now, the Taubman Institute funding will help his team genetically engineer a mouse that will allow them to explore in detail how exactly this enzyme and its genetically engineered variants work during a blood vessel disruption.

The Taubman funding may also help the team study this same enzyme in people. For instance, they may look for tiny variations in the gene for this enzyme among human heart attack and stroke patients, or among people who have cardiovascular risk factors but have not suffered a clot-related illness. Perhaps some variations in this enzyme predispose a person to clots, while other variations help protect them. And those variations could also form the basis for future treatment.

“What this funding will do is allow creative people to just take wild hypotheses that are based on a lot of intuition,” says Pinsky. “If you want to follow a hunch, this allows us to follow a hundred hunches -- which is something that other funding doesn’t allow you to do that often.

“This kind of resource is so completely flexible, and that’s truly a gift,” he adds. While his grants from federal agencies and other sources are important, they fund defined projects. “What very flexible money like this allows a lab such as mine to do is to really think out of the box, and think creatively. Often we do one experiment that leads us into a completely different area. This allows us the flexibility to really follow our noses and that makes science very exciting.”

Yehoash Raphael: Toward a cure for deafness
Scientist’s team is exploring revolutionary strategy to restore hearing

Yehoash Raphael
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Inner-ear biologist Yehoash Raphael, Ph.D., wants to pull off an audacious feat. In animals, and later in people, he hopes to discover how to insert stem cells into deafened inner ears, and coax tissues there to regenerate the lost hair cells that are crucial to hearing.

For the hundreds of millions of people worldwide who suffer from partial or total hearing loss, the benefits could be huge -- though Raphael cautions that this goal is still many years away. For now, hearing aids and cochlear implants help many, but the new concept that his team will pursue with Taubman Institute funding could accelerate a promising option for a large number of deaf people.

Hair cells are the essential conveyors of sounds in the ear. To make them grow again, Raphael and a multidisciplinary team first need to develop successful methods to plant and grow stem cells in the inner ear. It’s a complex, untried process that will involve gene transfer and tissue engineering.

Cancer Cells
In this picture of cells cultured by the Raphael-Kohrman team, the green cells are newly introduced cells that have become integrated into an existing layer of cells. This integration is crucial for the goal of restoring hearing by growing new hair cells in the damaged inner ears of deaf people. Now, this cell culture model will be used to design new ways to enhance the integration of newly introduced cells, which may open the door for the use of stem cells as a therapy for deafness.

First, the multidisciplinary team, with the help of David Kohrman, Ph.D., associate professor in otolaryngology and human genetics at the U-M Medical School, will develop methods that work in cell cultures. Then the team will move to animal tests, drawing on the expertise of other researchers in the Kresge Hearing Research Institute.

Raphael specializes in inner-ear biology, hereditary inner ear disease and restoring function in deaf ears. He heads the Otopathology Laboratory at Kresge and is the R. Jamison and Betty Williams Professor of Otolaryngology at the U-M Medical School.

In a recent breakthrough, he and his team used gene transfer techniques to regenerate hair cells and restore hearing in guinea pigs. In these guinea pig ears, hair cells were missing but other supporting cells remained in place, Raphael says. When inner ear trauma is very severe, however, even supporting cells are eliminated. In such cases, gene transfer does not work well, and the only hope for restoring the hair cells is the use of stem cell technology. The Taubman-sponsored work is aimed at treating those severely traumatized ears.

Stem-cell-based therapy for hearing loss is a new idea that is generating excitement among scientists. “This is a pretty radical and innovative approach,” the kind of untested idea that traditional funding agencies don’t usually support, says Raphael. He says he and his colleagues are extremely grateful for the funding and also the personal interest that Mr. Taubman has taken in the project. “His involvement, keen interest and understanding are very energizing,” he says.

The stem cells used in the early phases of the team’s work were animal stem cells. In deaf inner ears where hair cells and other supporting cells are gone, there remains only a diminished base of primitive cells.

It will be a big challenge to get these existing cells to accept the stem cells. “Imagine tiles on a floor,” he says. “Cells in the ear are connected to each other like a set of tiles. You need to engineer the existing tiles to open up and receive the newcomers.” Also, the stem cells themselves will need to be manipulated to allow them to integrate in the deaf ear.  The Taubman Institute grant will make this work possible, and pave the way for further funding from other sources. Raphael says, “If we make good progress in cell culture and get our techniques to work in guinea pigs, I’ll be delighted.”

Max Wicha: Targeting stem cells in cancer
Taubman gift will allow for integrated research in cancer stem cells

Max Wicha
Hear Dr. Wicha Speak

Cancer stem cells are the small number of cancer cells that fuel the growth of new tumor cells. Finding drugs that target and kill these adult stem cells could dramatically improve cancer treatment.

Max Wicha, M.D., director of the University of Michigan Comprehensive Cancer Center and Distinguished Professor of Oncology, will use his funding from the Taubman Institute to expand the integrated research across cancer types focusing on cancer stem cells.

“The goal of all our existing therapies has been to kill as many cells within the tumor as possible. The current model may lead to treatments limited in their effectiveness, because we have not been targeting the most important cells in the tumor – the cancer stem cells. If we hope to cure more cancers we will need to target and eliminate this critical type of cancer cell,” Wicha says.

Wicha’s lab was part of the team that first discovered stem cells in breast cancer, the first described in any human solid tumor.

Since then, U-M researchers were also first to discover stem cells in pancreatic and head and neck cancers. U-M researchers are also focusing on cancer stem cells in virtually every cancer type, including colon, lung and thyroid tumors, as well as ongoing work in breast cancer.

Cancer Cells
This image shows two types of cells isolated from human breast cancers by U-M scientists. The top image is of cells that have lost the ability to spread and form tumors, while the lower image shows cancer stem cells. Courtesy of Proceedings of the National Academy of Sciences.

“The lessens we’ve learned from breast cancer stem cells will be very valuable to us as we attack the cancer stem cells in these other organs. Our hope is that some of the treatments we develop for one type of tumor like breast cancer may also work in targeting the cancer stem cells in these other types of tumors, and so we actually may make great progress in treating a wide variety of cancers,” Wicha says.

The Taubman Scholars gift will be used to further the research and stimulate interaction among the many researchers throughout the Cancer Center who are focusing on this issue.

“We have the opportunity to be the world leader in this emerging area of cancer research. The Taubman Scholars support will enable us to extend that work at a much more rapid pace, bringing these discoveries in cancer stem cells into the clinic much more rapidly,” Wicha says. “I am excited about the potential of taking these discoveries being made in the laboratory and actually applying them to clinical trials and treatments for patients. Ultimately the benefit of the Taubman money will be seen by our patients through development of more effective treatments for their cancers.”

 

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