BreakThrough Digest Medical News

Posted: 01 Jun 2013 09:00 PM PDT

Prometheus, the mythological figure who stole fire from the gods, was punished for this theft by being bound to a rock. Each day, an eagle swept down and fed on his liver, which then grew back to be eaten again the next day.

Modern scientists know there is a grain of truth to the tale, says MIT engineer Sangeeta Bhatia: The liver can indeed regenerate itself if part of it is removed. However, researchers trying to exploit that ability in hopes of producing artificial liver tissue for transplantation have repeatedly been stymied: Mature liver cells, known as hepatocytes, quickly lose their normal function when removed from the body.

“It’s a paradox because we know liver cells are capable of growing, but somehow we can’t get them to grow” outside the body, says Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT, a senior associate member of the Broad Institute and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

Now, Bhatia and colleagues have taken a step toward that goal. In a paper appearing in the June 2 issue of Nature Chemical Biology, they have identified a dozen chemical compounds that can help liver cells not only maintain their normal function while grown in a lab dish, but also multiply to produce new tissue.

Cells grown this way could help researchers develop engineered tissue to treat many of the 500 million people suffering from chronic liver diseases such as hepatitis C, according to the researchers.

Lead author of the paper is Jing (Meghan) Shan, a graduate student in the Harvard-MIT Division of Health Sciences and Technology. Members of Bhatia’s lab collaborated with researchers from the Broad Institute, Harvard Medical School and the University of Wisconsin.

Bhatia has previously developed a way to temporarily maintain normal liver-cell function after those cells are removed from the body, by precisely intermingling them with mouse fibroblast cells. For this study, funded by the National Institutes of Health and Howard Hughes Medical Institute, the research team adapted the system so that the liver cells could grow, in layers with the fibroblast cells, in small depressions in a lab dish. This allowed the researchers to perform large-scale, rapid studies of how 12,500 different chemicals affect liver-cell growth and function.

The liver has about 500 functions, divided into four general categories: drug detoxification, energy metabolism, protein synthesis and bile production. David Thomas, an associate researcher working with Todd Golub at the Broad Institute, measured expression levels of 83 liver enzymes representing some of the most finicky functions to maintain.

After screening thousands of liver cells from eight different tissue donors, the researchers identified 12 compounds that helped the cells maintain those functions, promoted liver cell division, or both.

Two of those compounds seemed to work especially well in cells from younger donors, so the researchers ? including Robert Schwartz, an IMES postdoc, and Stephen Duncan, a professor of human and molecular genetics at the University of Wisconsin ? also tested them in liver cells generated from induced pluripotent stem cells (iPSCs). Scientists have tried to create hepatocytes from iPSCs before, but such cells don’t usually reach a fully mature state. However, when treated with those two compounds, the cells matured more completely.

Bhatia and her team wonder whether these compounds might launch a universal maturation program that could influence other types of cells as well. Other researchers are now testing them in a variety of cell types generated from iPSCs.

In future studies, the MIT team plans to embed the treated liver cells on polymer tissue scaffolds and implant them in mice, to test whether they could be used as replacement liver tissues. They are also pursuing the possibility of developing the compounds as drugs to help regenerate patients’ own liver tissues, working with Trista North and Wolfram Goessling of Harvard Medical School.

Bhatia and colleagues have also recently made progress toward solving another challenge of engineering liver tissue, which is getting the recipient’s body to grow blood vessels to supply the new tissue with oxygen and nutrients. In a paper published in the Proceedings of the National Academy of Sciences in April, Bhatia and Christopher Chen, a professor at the University of Pennsylvania, showed that if preformed cords of endothelial cells are embedded into the tissue, they will rapidly grow into arrays of blood vessels after the tissue is implanted.

To achieve this, Kelly Stevens in the Bhatia lab worked with Peter Zandstra at the University of Toronto to design a new system that allows them to create 3-D engineered tissue and precisely control the placement of different cell types within the tissue. This approach, described in the journal Nature Communications in May, allows the engineered tissue to function better with the host tissue.

“Together, these papers offer a path forward to solve two of the longstanding challenges in liver tissue engineering ? growing a large supply of liver cells outside the body and getting the tissues to graft to the transplant recipient,” Bhatia says.

Contact: Sarah McDonnell
s_mcd@mit.edu
617-253-8923
Massachusetts Institute of Technology

Written by Anne Trafton, MIT News Office

New cancer drug shows promise for treating advanced melanoma

Posted: 01 Jun 2013 09:00 PM PDT

Researchers from UCLA’s Jonsson Comprehensive Cancer Center report that a new drug in preliminary tests has shown promising results with very manageable side effects for treating patients with melanoma, the deadliest form of skin cancer.

The results were presented at the 2013 meeting of the American Society of Clinical Oncology today in Chicago by Dr. Antoni Ribas, professor of medicine in the UCLA division of hematology-oncology, who led the research. Following Ribas’ presentation, the study was published online ahead of press in the New England Journal of Medicine.

The results are from the first clinical trial of the drug lambrolizumab (MK3475), which was discovered and developed by Merck. Researchers analyzed 135 patients with advanced metastatic melanoma who were divided into three groups with different treatment regimens.

Overall, 38 percent of patients taking lambrolizumab saw confirmed improvement of their cancer across all dose levels. Of those taking the lowest dose of lambrolizumab, 25 percent showed improvement, while 52 percent of those who received the highest dose improved. The rate of any tumor response across all patients was 77 percent. Researchers have not yet determined the average duration of response to the drug, because only five patients who had initial responses were taken off the study after their cancers got worse. To date, the longest response has been over one year.

Side effects with lambrolizumab are usually mild and easily managed. These include fatigue, fever, skin rash, loss of skin color and muscle weakness. Thirteen percent of patients had side effects that were more severe, including inflammation of the lung or kidney, and thyroid problems.

“This study is showing the highest rate of durable melanoma responses of any drug we have tested thus far for melanoma, and it is doing it without serious side effects in the great majority of patients,” Ribas said.

Serving as the immune system’s soldiers, T cells find and destroy invaders that cause infections and diseases. Cancers like melanoma are usually not detected by the immune system, and they spread without T cells destroying them. One problem may be that a protein called PD-L1 on the surface of cancer cells allows them to hide from T cells that express the protein PD-1 on their surfaces.

Lambrolizumab is an antibody that blocks PD-1 and reactivates an immune response to the cancer cells.

“Lambrolizumab turns on the body’s immune system to attack the cancer, and the immune system seems to remember that the melanoma is the enemy and continues to control it long term,” Ribas states.

These data have led to a series of additional studies testing lambrolizumab in patients with melanoma and other cancers, including lung cancer.

Lambrolizumab received “breakthrough therapy” designation from the U.S. Food and Drug Administration in April. Enacted as part of the 2012 FDA Safety and Innovation Act, the breakthrough therapy designation was created by the agency to expedite the development and review of a potential new medicine if it is “intended, alone or in combination with one or more other drugs, to treat a serious of life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.”

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This research was supported by Merck Sharp & Dohme Corp. The UCLA authors have no financial ties to disclose.

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

Contact: Shaun Mason
smason@mednet.ucla.edu
University of California – Los Angeles