Immunologists receive $4.8M grant to target multiple diseases by manipulating enzyme

Immunologists Barbara A. Osborne and Lisa M. Minter at the University of Massachusetts Amherst, as part of a multi-institution research team, will share a five-year, $4.8 million National Cancer Institute grant to target multiple diseases including cancer, Alzheimer's and graft-versus-host disease (GVHD) by manipulating an enzyme that activates over 100 different protein substrates in the body.

The NCI program project grant supports groups of investigators at four different laboratories, two at UMass Amherst, one at the University of Mississippi Medical School and one at the University of Florida, who work in different systems but approach disease-related problems from different perspectives, Osborne says.

"We are all interested in an enzyme called gamma secretase (GS)," she explains. "When it acts by cleaving or cutting proteins, many different substrates are activated, including a very important one called NOTCH1. Both Lisa and I have shown, first in a mouse model of multiple sclerosis, that NOTCH1 deregulation leads to many autoimmune diseases."

Their counterpart at Mississippi has shown that many cancers overexpress NOTCH1 and in many settings it drives tumor development, Osborne adds. The research group in Florida has found aberrant GS cleavage of a substrate called APP leads to amyloid plaque formation. "So GS is involved in a number of diseases and we want to know more about how it functions," the immunologist notes.

Minter says, "We thought if we could block GS, inhibit it, that could be useful in a variety of different disease settings. We'd like to fine-tune its inhibition, creating a very precise tool that can stop overexpression of a substrate such as NOTCH and its variants involved in breast cancer, for example, while not inhibiting its actions in the immune system."

Eventually the UMass Amherst researchers, working with colleagues in chemistry and polymer science, would like to develop a biosensor-controlled nanogel that could send GS inhibitors to a specific area in the body and release them at the appropriate moment to fight aberrant cancer or other cells.

But at present many challenges remain, says Osborne, though they do know that GS has the ability to cut and activate a surprising number of protein substrates. "We don't really understand how it knows to cleave some protein substrates and not others. There's nothing obvious that says, 'This is a substrate for GS,' so we can't recognize them. It's a head scratcher; we know if we inhibit GS we can see effects on all kinds of different areas, but the challenge is we can't see how it identifies its targets."

Protein substrate targets for most enzymes are recognizable and are very specific, Minter explains, but not GS. "Your cells get a lot of mileage out of GS, and that's probably why it's so important biologically. But if we inhibit it globally, it's a disaster. All kinds of essential functions come to a halt."

"If we can figure out a way to specifically target some substrates and not others, to control the activity of the enzyme in time and space to maintain beneficial immune system activity which is attacking diseased cells, it would be a great advance." The two UMass Amherst researchers have designed five years of experiments that will involve five or six graduate students working in the two labs.

Minter and Osborne use mouse disease models such as aplastic anemia and GVHD to explore GS action. "Right now, bone marrow transplant is curative for leukemia, but it is only a last ditch effort because of GVHD. It is an enormous clinical problem," Osborne says. They hope to inhibit GS in leukemic mice transplanted with healthy cells to prevent the transferred cells' immune factors from attacking host tissue at the same time they are attacking the leukemic ones.

"We want the transferred cells to attack the leukemia but not the host. We're pretty sure we can do this with GS inhibitors, and this is a major first aim of the grant. It has really great potential benefit for human health by preventing rejection and GVHD."

Source: University of Massachusetts