Inflammation a Common Theme for U-M Researchers
Researchers at the University of Michigan are currently collaborating with Takeda Pharmaceuticals on a $250k+ Phase III clinical trial of vedolizumab, a promising new drug that treats the inflammatory symptoms of ulcerative colitis and Crohn's Disease. This is just one example of how industry insiders are learning that U-M's strength in inflammation makes us a valuable partner in a growing area of therapeutics.

In the last decade, researchers and clinicians have come to a greater understanding of chronic inflammation and its role in human diseases. In addition to the vedolizumab trial, UMMS faculty are collaborating across a spectrum of disciplines that have a common denominator in inflammation. For instance, Terry Smith, Ph.D. and Raymond Douglas, Ph.D. of the U-M Kellogg Eye Center have recently identified an immune link to inflammation and scarring in patients with Graves' disease. Jonathan Rubin, M.D., Ph.D.. of Gastroenterology is using new imaging methods to study whether Crohn's patients exhibit fibrosis, which requires surgery; or inflammation, which can be treated with drugs. And faculty at the U-M Comprehensive Cancer Center are conducting a clinical trial to determine if ginger root supplements can reduce colon inflammation, and thus act as a colon cancer prevention agent.

Peter Higgins, M.D., Ph.D., M.Sc. is the lead investigator on the vedolizumab trial and involved with other inflammation-related research at the U-M, including a recent study that indicates certain stomach bacteria may fight inflammatory bowel disease caused by salmonella. "Learning more about how to successfully treat Crohn's patients, it's easy to picture a path where what we learn can be applied to treating inflammation related to cancer or Alzheimer's," notes Higgins.

From diseases like rheumatoid arthritis and dermatological conditions to cancer and metabolic diseases, every day we're gaining a clearer picture of inflammation as an underlying contributor to many disorders. As a recognized leader in oncology, neuroscience, cardiovascular, and metabolic diseases, the U-M offers potential strategic partners a "team science" approach where we are uniquely equipped to focus on how inflammation factors in these areas. "Our breadth of research strength across diseases differentiates U-M," notes Steven Kunkel, Ph.D. and Senior Associate Dean for Research. "From our work in cellular and molecular mechanisms, to our novel animal models, to our diverse patient populations for translational research, we bring a powerful arsenal to bear on learning how inflammation impacts a wide variety of diseases."

Story credit: Ann Curtis, UMMS Business Development

Companies Value U-M's Novel Animal Models
While many research institutions work with mouse and rat models, the University of Michigan offers access to a variety of animal models that are uniquely suited to investigating human disease. Researchers at the U-M Cardiovascular Center (CVC) and a major pharmaceutical company are collaborating on a new $250,000 project that takes advantage of the fact that sheep are excellent models for cardiovascular disorders. This sheep model is one of several used by the Center for Arrhythmia Research (part of the CVC), which studies many aspects of cardiac arrhythmias. "Our access to clinically relevant animal models can't be overstated," notes Jose Jalife, M.D., Co-director of the Arrhythmia Center. "Plus we offer commercial partners an integrated, multi-scale approach that maximizes their project investment."

Sandeep Pandit,, Ph.D., is the lead investigator testing an experimental drug from the company that would treat atrial fibrillation (Afib). Afib is the most common cardiac arrhythmia encountered in the clinic, affects nearly two million Americans, and increases the risk of stroke and heart failure. In patients with Afib, the electrical activity in the atria is very rapid, sometimes up to 500 beats per minute (bpm) or more, compared to the normal rate of 60-90 bpm.

Pandit and his team are focusing on understanding the ionic mechanisms that initiate and maintain the fast Afib activation rates, in both paroxysmal and chronic Afib. With the similarity to humans in terms of the atrial electrical activity and the underlying ion channels, sheep represent an optimal experimental animal model. The sheep can be outfitted with pacemakers to create a model of chronic Afib, and it's also possible to create paroxysmal Afib in the isolated heart using acute chemical interventions. Sophisticated optical imaging techniques are used to study the impulse propagation in the heart, and cellular experiments examine the main ion channels responsible for sustaining Afib. CVC researchers plan to utilize biophysically detailed mathematical models to interpret and analyze the experimental data. This integrated approach will offer the pharmaceutical company insight into the efficacy, as well as the strengths and weaknesses, of their potential new drug.

"Many drugs currently on the market are not very effective in treating Afib," notes Pandit. "Our research using sheep models provides insight into whether the company's new drug can offer a more promising therapy for Afib that will ultimately save lives."

The U-M animal care and use program maintains full compliance with federal and state regulations and policies, as well as nationally accepted professional standards, and has maintained uninterrupted accreditation by the Association for Assessment and Accreditation of Laboratory Animal Care, International since originally accredited in 1971.

Story credit: Ann Curtis, UMMS Business Development

Cancer Stem Cell Vaccine in Development Shows Antitumor Effect
Scientists from the U-M Comprehensive Cancer Center may have discovered a new paradigm for immunotherapy against cancer by priming antibodies and T cells with cancer stem cells, according to a study published in Cancer Research, a journal of the American Association for Cancer Research.

"This is a major breakthrough in immunotherapy research because we were able to use purified cancer stem cells to generate a vaccine, which strengthened the potency of antibodies and T cells that selectively targeted cancer stem cells," said Qiao Li, Ph.D., a research assistant professor of surgery at the U-M Medical School.

Cancer stem cells are tumor cells that remain present, and ultimately resistant, after chemotherapy or radiation treatment. Scientists disagree on whether these cells have unique properties, but those who support the uniqueness idea have argued that these cells regenerate the tumors that lead to relapse. Despite the similar name, cancer stem cells are distinct from embryonic stem cells, and the two avenues of research are separate.

For the current study, Li and colleagues extracted cancer stem cells from two immunocompetent mouse models and used them to prepare the vaccine. "We found that these enriched cancer stem cells were immunogenic and far more effective as an antigen source compared with the unselected tumor cells normally used in previous immunotherapy trials," said Li. "The mechanistic investigations found that when antibodies were primed with cancer stem cells, they were capable of targeting cancer stem cells and conferring antitumor immunity."

The researchers also found that cytotoxic T lymphocytes harvested from cancer stem cell-vaccinated hosts were capable of killing cancer stem cells in vitro.

Story credit: Nicole Fawcett, UMHS PRMC