Larry Matherly, Ph.D., professor of Pharmacology for the Wayne State University School of Medicine and the Barbara Ann Karmanos Cancer Institute, has been awarded a $50,000 Pediatric Oncology Research Grant by the St. Baldrick’s Foundation.

Dr. Matherly, who also serves associate director of the graduate program in cancer biology, received the grant for his research project titled “NOTCH Signaling and therapy of T-cell leukemia in children.” He hopes the research will establish the extent to which NOTCH1 mutations predict clinical outcomes in T-cell ALL and identify new approaches for treating T-cell ALL in children.

“Our project is an extension of our established translational research program in the biology of childhood leukemia at the Karmanos Cancer Institute and the Children's Hospital of Michigan, and is a paradigm for translational research in that it involves close collaboration between basic Ph.D. researchers and practicing oncologists,” Dr. Matherly said. “It is this unique working arrangement which, in itself, provides the major conduit for translating laboratory results on primary patient specimens back to patients.”

The St. Baldrick's Foundation is a non-profit organization dedicated to raising money for childhood cancer research. The foundation coordinates worldwide head-shaving events in which volunteers raise donations to support childhood cancer research.

The grant to Dr. Matherly is part of more than $12.6 million awarded by the foundation for pediatric oncology research.

A Wayne State University School of Medicine transplant team is offering new hope to HIV-positive patients suffering kidney failure.

A team led by Scott A. Gruber, M.D., Ph.D., M.B.A, F.A.C.S., F.C.P., performed the first two renal kidney transplants in HIV-positive patients in the state of Michigan. He and his team at Harper University Hospital have gone on to perform an additional seven kidney transplants for patients with HIV, with vastly lowered incidence of infection and rejection.

Dr. Gruber’s protocol and findings were published in July in Transplantation, one of two major journals in the field of transplant surgery. The publication in Transplantation centers on Dr. Gruber’s results with the first eight patients.

Only two other transplant centers in the U.S. – Drexel University and the University of California, San Francisco – have reported results on a larger number of such cases, said Dr. Gruber, professor and chief of the Section of Transplant Surgery for the Wayne State University School of Medicine, and director of the Organ Transplant Program at Harper University Hospital.

The patients who received the transplanted kidneys were required to have had CD4 counts above 200 cells/mm3 and an ultrasensitive viral load for HIV below 50 copies/ml for at least six months while receiving highly active antiretroviral therapy (HAART).

“HIV positivity is still considered an absolute contraindication to renal transplantation in most transplant centers,” Dr. Gruber said. “This stems from the fear that further immunosuppressing these patients with pharmacologic agents, over and above their baseline state of immunosuppression from the disease itself, would produce an unacceptably high risk of infections and malignancy. However, this has not proven to be the case in patients who are maintained on HAART therapy with adequate cell counts and suppression of the virus.

“HIV-positive patients are no longer dying rapidly from AIDS, can have prolonged survival and may even develop renal failure over the long term on the basis of their HIV infection,” he added. “There is no longer any reason to deny the appropriate HIV-positive candidate a chance at receiving a kidney transplant.”

Many transplant centers, he noted, harbor concerns regarding the close monitoring HIV-positive patients require due to powerful drug interactions between the HAART medications and the immunosuppressive agents required to reduce the chance of transplant rejection. “We are very fortunate here at Wayne State to have assembled a team of experts to help care for these most challenging patients, with active participation from transplant surgery, nephrology, infectious disease and pharmacy,” he said.

While HIV-positive patients previously were not considered viable for kidney transplantation, when suffering organ failure – either from the disease or other causes – they were maintained on dialysis.

“However, just like HIV-negative patients, the quality of life on dialysis is poorer and the results of renal transplantation for appropriately chosen HIV-positive candidates are superior to those of remaining on dialysis,” Dr. Gruber said. “Why should such candidates be deprived of this option?”

Four centers, Dr. Gruber said, previously reported results with renal transplantation in HIV-positive recipients on HAART therapy, with the incidence of acute rejection ranging from 43 percent to 67 percent. These rejection rates were much higher than those for HIV-negative patients (15 percent to 20 percent). “For the first time, we were able to achieve a low incidence of acute rejection (13 percent), equivalent to that observed in HIV-negative patients,” Dr. Gruber said.

Dr. Gruber and his team achieved the lowered infection and rejection rates by introducing three modifications to the regimens used by others: adding an anti-interleukin-2 receptor antibody for induction of immunosuppression; increasing the initial target blood levels of cyclosporine, the main immunosuppressive drug around which the maintenance anti-rejection protocol is based; and adjusting the dose of another anti-rejection medication, mycophenolate mofetil (Cellcept), according to blood levels obtained beginning at two to four weeks, and up to six months following transplantation.

Dr. Gruber said the program will move forward with further kidney transplants in HIV-positive patients using the same protocol. He has several such patients on the list awaiting receipt of a suitable kidney.

More than 600 people gathered to honor a Wayne State University School of Medicine alum who serves as president of the Holocaust Memorial Center Zekelman Family Campus.

The center’s 24th anniversary celebration recognized the leadership of Michael Treblin, M.D., who has been involved with the Farmington Hills center for nine years.

Dr. Treblin, a 1979 graduate of the School of Medicine, has served as president of the center for four years, “and I plan to be involved indefinitely,” he said.

"This honor represents years of devotion to a cause dear to my heart,” said Dr. Treblin, a pediatrician at Pediatrics Consultants of Troy, in Shelby Township. “I feel overwhelming pride.”

His father, Joseph, who will turn 89 this month, is a Holocaust survivor. The senior Treblin attended the Sept. 14 celebration.

“I have an unabated passion that the victims of the Holocaust are never forgotten,” Dr. Treblin said. “The prejudice and intolerance of the Holocaust translate to present times. People must know that prejudice and intolerance are incompatible with a healthy society. The Holocaust Memorial Center remembers and teaches.”

The center will soon develop a children’s gallery to tell the story of the Holocaust in an age-appropriate fashion. In addition, the center will erect a memorial tomb.

“As president, Dr. Treblin demonstrated a form of leadership and commitment that may rightfully be the envy of any institution,” said center founder and CEO, the Rabbi Charles H. Rosenzveig. “… We are honoring Dr. Treblin not only for his exemplary leadership as president of our institution, but also for his continuous inspiring devotion to its causes.”

Researchers at the Wayne State University School of Medicine and the Barbara Ann Karmanos Cancer Institute have developed an HER2 DNA cancer vaccine that has shown to be effective on drug-resistant tumors in mice. The study was reported in the Sept. 15 issue of Cancer Research, a journal of the American Association for Cancer Research.

The vaccine, researchers said, completely eliminated HER2-positive tumors – including cancers resistant to current anti-HER2 therapy – in mice, without any toxicity.

The study suggests the vaccine could treat women with HER2-positive, treatment-resistant cancer or help prevent cancer recurrence. The researchers also said it might potentially be used in cancer-free women to prevent initial development of these tumors.

Wei-Zen Wei, Ph.D., professor at the Barbara Ann Karmanos Cancer Institute and Department of Immunology and Microbiology at the School of Medicine, together with a team of researchers, has been working on a series of cancer-fighting vaccines since 1996 to help prevent HER2-positive breast cancer.

Approximately 20 percent to 30 percent of breast cancers make too much of the protein HER2, which is made at low levels by normal breast cells. Tumors that overexpress HER2 (called HER2-positive) tend to grow faster and are more likely to return than tumors that don’t overexpress the protein.

Dr. Wei said this vaccine was tested in the laboratory on tumor cells that no longer responded to other therapies for HER2-positive breast cancer. The results in mice showed that the vaccine prevented cancer growth and was not toxic.

“We each have an immune system to help fight off disease,” Dr. Wei explained. “However, when cancer develops, the immune system can’t always distinguish tumor cells from normal cells, so the full power of the immune system is not harnessed to fight the disease. This vaccine helps to educate the immune system so that it recognizes HER2-positive cancer cells, helps destroy them and prevents them from spreading.”

The vaccine consists of “naked” DNA -- genes that produce the HER2 receptor -- as well as an immune stimulant. The researchers used pulses of electricity to deliver the injected vaccine into leg muscles in mice, where the gene produced a huge quantity of HER2 receptors that activated both antibodies and killer T cells.

“While HER2 receptors are not usually seen by the immune system when they are expressed at low level on the surface of normal cells, a sudden flood of receptors alerts the body to an invasion that needs to be eliminated,” Dr. Wei said. “During that process, the immune system learns to attack cancer cells that display large numbers of these receptors.”

Dr. Wei and her colleagues also used an agent that temporarily suppressed the activity of regulatory T cells, which normally keeps the immune system from over-reacting. In the absence of regulatory T cells, the immune system responded much more strongly to the vaccine. When the researchers implanted HER2-positive breast tumors in the mice, the cancer was eradicated.

“The immune response against HER2-positive receptors we saw in this study is powerful, and works even in tumors that are resistant to current therapies,” she said. “The vaccine could potentially eliminate the need to even use these therapies.

“Both tumor cells that respond to current targeted therapies and those that are resistant to these treatments were eradicated,” Dr. Wei said. “This may be an answer for women with these tumors who become resistant to the current therapies.

“As we continue our extensive research on this promising vaccine, based on the results to date, we believe this could eventually help control the spread of HER2-positive breast cancer in patients who have been resistant to other treatments, and possibly prevent HER2-positive breast cancer from occurring. The greatest power of vaccination is protection against initial cancer development, and that is our ultimate goal with this treatment,” Dr. Wei said.

Dr. Wei’s lab is the first to develop HER2 DNA vaccines. The first vaccine was developed in 1999. In collaboration with the Karolinska Institute in Stockholm, Sweden, a pilot clinical trial with the HER2 DNA vaccine has been conducted in patients with Stage IV breast cancer and has demonstrated safety. Further testing is being considered.

Other researchers working with Dr. Wei include Paula J. Whittington, Marie P. Piechocki, Henry H. Heng, Jennifer B. Jacob, Richard F. Jones and Jessica B. Back. Ms. Whittington is an M.D./Ph.D student in her third year clerkship at the School of Medicine. She is cited as the first author of the publication.

A monetary gift by an anonymous donor has completed the Wayne State University School of Medicine’s efforts to capture a $3 million Kresge Foundation grant to assist in the construction of the Richard J. Mazurek, M.D., Education Commons, the new face of medical education in Michigan.

The donor's commitment represents a significant investment in medical education and metropolitan Detroit, said School of Medicine Dean Robert M. Mentzer Jr., M.D.

The donor, who wished to remain anonymous, helped finalize the campaign goal of $30 million for the new state-of-the-science facility.

The donor asked that the pledge be used to honor Raymond Margherio, M.D., who graduated from the School of Medicine in 1965.

“This gift means so much to the School of Medicine, and to the future of medical education and healthcare,” said Dean Mentzer. “The donor’s foresight and commitment to the School, the residents of the community and to medicine will help establish the foundation for the next generation of medical education in Michigan.”

The Margherio Family Conference Center will serve as an education center for the future leaders and innovators in medicine, and as a focal meeting place for community groups.

The center will seat up to 120, and will contain eight alcoves along its perimeter to accommodate break-out study sessions. Each alcove will boast a plasma screen and computer, providing students access to online diagnostic resources to research topics ranging from diabetes to women’s health issues. Grand Rounds can also take place there, allowing physicians to present unusual cases. The two projection screens are so technologically advanced that physicians will be able to display large images, such as X-rays or pathology specimens, with microscopic precision from almost any angle. The hub’s user-friendly technology will easily display material with great accuracy so students can witness, for example, close-up footage of surgery.

Physicians will take advantage of continuing medical education opportunities in the center as well, whether in classes or by actual testing. Sixty percent of all southeastern Michigan physicians receive all or part of their medical training at Wayne State University, and the center is designed to directly serve that population. The center’s flexibility allows it to accommodate the Southeast Michigan Center for Medical Education. A hospital consortium that includes numerous teaching hospitals from the metropolitan Detroit area, SEMCE organizes programs in every specialty for residents, fellows and practicing physicians.

Education beyond the traditional classroom will be taught in the center regularly, with an emphasis on commitment to community. The head of a hospice will speak. Directors from numerous organizations, including the Cass Clinic, the Triangle Foundation and Covenant House, will lecture. These are some of the experts who address first- and second-year medical students enrolled in the Co-Curricular for Credit Program, which helps raise student awareness as they volunteer in the Detroit community. Participants learn firsthand about the people who become their patients, they see the health disparities in our communities and gain new-found empathy as they witness a new perspective. This humanistic approach to medicine has proved so successful that Saturday morning presentations are packed by more than 100 students, making the center the ideal place for such learning.

Other events can take place here as well, including Med Ed Prep, a four-week community outreach course designed to give students 16 and older a taste of medical school.

The Margherio Family Conference Center will quickly become the epicenter of the School of Medicine, and will develop a legacy as the incubator of the physicians and community volunteers of tomorrow.

A Wayne State University School of Medicine researcher has secured a $700,000 grant from the National Multiple Sclerosis Society of America to develop a mouse model that could lead to testing of new drugs to treat stress that can exacerbate MS.

Alexander Gow, Ph.D., associate professor in the School of Medicine’s Center for Molecular Medicine and Genetics, the Carman and Ann Adams Department of Pediatrics, and the Department of Neurology, will use the four-year grant to generate a non-immune animal model of multiple sclerosis.

Because MS and similar diseases do not occur in animals, Dr. Gow said, researchers must first establish an animal model with a weakened immune system for testing. Once the animal model is established, Dr. Gow can use the mice to determine how the disease gets started, study its pathology and then design drugs to alleviate the symptoms.

MS is considered an autoimmune disease. The body’s own immune system attacks the brain and gradually destroys it, typically over many years.

“An obvious treatment for such a disease is to suppress the immune system so it won’t attack the brain,” Dr. Gow explained, “and such a treatment is in common use, using steroids. This treatment does improve the disease symptoms, but only in the short term. The long-term prognosis is unchanged.”

Since immune suppression is not a cure, Dr. Gow’s lab has been investigating metabolic stress as a factor in the disease process. He said there is “good evidence” that cells in the brain damaged by MS – cells called oligodendrocytes – experience the stress. Dr. Gow is studying a mouse with a genetic mutation that causes metabolic stress in oligodendrocytes. His lab has been characterizing the effect of stress on the cells, and has engineered a new gene into the Rumpshaker Mutant Mouse (RSH). The Trb3 gene appears to relieve the stress, and RSH mice that also have the gene show milder disease symptoms than RSH mice without that gene.

The National Multiple Sclerosis Society of America grant will allow Dr. Gow’s lab to complete the characterization of the mice and determine the biological function of the Trb3 gene.

"This is an important study to investigate whether MS causes myelin-making cells to self-destruct, and if so, find ways to block this process," said Dr. Patricia A. O’Looney, vice president of Biomedical Research for the National Multiple Sclerosis Society.

Once he determines the biological function of the Trb3 gene in oligodendrocytes, “we will probably know how this gene reduces the disease symptoms of RSH mice,” Dr. Gow explained. “Next, we will look for drugs that mimic the activity of the Trb3 gene and use them on the RSH mice. If those tests identify useful drugs, we will be in a position to begin pre-clinical trials for MS.”

Eventually, Dr. Gow said, he hopes that the drugs identified as reducing oligodendrocyte stress in the mice can then be tested in MS patients.

“Because there are no similar approaches to MS treatments, the drugs may move fairly rapidly through the trial process,” he said. “We will focus on drugs that are already in pre-clinical or clinical trials, which should move the drug trials along fairly quickly.

“I can’t overemphasize the timeliness of these grants for our work. We are on the verge of significant advances in these diseases, but federal government policies toward medical research over the last four to six years have been so harsh that it has become very difficult to continue research on rare diseases,” Dr. Gow said. “The National Institutes of Health simply has insufficient funds to support such research.”