Sugar anything but sweet on cancer, chemistry researcher provesBy Cynthia Nowak : October 4th, 2012
Carbs as cancer fighters? They could represent the next wave of treatment for the disease. As medical researchers worldwide race to develop a viable cancer vaccine, a UT chemistry lab headed by Dr. Peter Andreana has identified a promising new approach that enlists carbohydrates.Andreana, a professor in the Department of Chemistry who joined UT earlier this year from Wayne State University, was quick to explain the split between pasta-and-pastries carbs that can derail a diet plan and the tumor-associated carbohydrate antigens being studied in his lab under a $1.5 million, five-year grant from the National Institutes of Health.
“Sugars — which are carbohydrates — can actually be beneficial from an immunological perspective,” he said, citing successes such as Pneumovax 23, a carbohydrate-based vaccine effective against streptococcus pneumonia.
Despite such victories in the fight against bacterial diseases, Andreana noted another arena: “Viral and chronic diseases such as malaria, cancer, HIV — can carbohydrates be used to mount an immunological attack against them?”
It’s not as though no one has made the attempt, he said, but thus far, such carbohydrate-based vaccines have failed. He believes he knows the reason.
First, a bit of basic biological chemistry. When invading pathogens attack, the human immune system responds with a layered system of natural defenses. Specific cell types play specialized roles in the immune response.
Some principal players: T cells, the white blood cells that figure prominently in the cell-mediated immune response; and B cells, which function in the humoral immune response (mediated by secreted antibodies).
Carbohydrates have long been known to elicit an immune response with B cells that commonly generate particular antibodies called IgM, Andreana explained. However, long-lasting immunity requires the engagement of T cells as well. If T cell stimulation was needed, proteins and peptides were the routes traditionally utilized in research models.
It’s worked well in the development of vaccines against bacterial diseases. However, success has been elusive in developing cancer vaccines.
That’s the quest on which Andreana and his team set their sights. “We sifted though a mass of research literature,” he said. “The majority of work done in the field of developing carbohydrate-based cancer vaccines has been done on the carbohydrate Thomsen-Nouveau antigen — Tn for short.”
Of the several carbohydrate-based antigens that exist on the surface of cancer cells, Tn is the simplest, making it easier for Andreana’s laboratory to synthesize its derivatives for testing.
During their review of related research, Andreana’s group found a paper showing for the first time that a T-cell-mediated immune response could be elicited by a capsular polysaccharide (PS A1) — which is a sugar, thus a carbohydrate — from a bacterial source existing in the human intestine.
“This was an enormous discovery — paradigm changing,” Andreana said.
“PS A1 is made up of repeating tetromaric units that grows to a size of 120 to 140 repeating units. The polysaccharide is unique in that it contains a special charge character, one that is believed to be responsible for its biological activity.
“I was captivated by the fact that these things are behaving like proteins. What if, I thought, we take advantage of this known motif?”
Thus, his research team chemically modified one of PS A1’s sugars to produce a semi-synthetic vaccine made up of PS A1 and cancer antigen Tn. Using a traditional immune study, they injected the modified carbohydrate-immunogen into mice.
What they found was extraordinary: The chemically modified polysaccharides evolved IgG3 antibodies — which are carb-specific and the result of isotype switching, the process necessary to T cells being activated.
“We were ecstatic,” Andreana recalled.
His team also determined that these antibodies generated in mice can bind to human tumor cells. They’ve published a paper this year on that topic.
Corroboration was needed, he said: “We’re just naive chemists, so when we first got some of these biological results, I didn’t even believe them. We connected with collaborators, including 21st Century Therapeutics and Henry Ford Health Systems. They were able to reproduce our results.”
A subsequent cyto-toxicity assay using human tumor cells in a Petri dish showed that the lab’s antibodies do have a function in killing the cells. In mice that cannot generate an immune response, injecting the antibodies resulted in slowed tumor growth.
As his team evolves into the area of immuno-therapeutics, Andreana’s optimism burns high: “We’re excited about bringing the NIH grant to The University of Toledo, not only to expand on the work we’ve done, but develop something new.
“In three years, I’d like to be able to come back and report we have IgG3 antibodies based on an entirely carbohydrate construct and they can be used to kill tumor cells effectively.”
Previous new models, he noted, resulted in drugs that include Rituxan to treat chronic lymphocytic leukemia and Herceptin for breast cancer. “As of six or seven years ago, there were only a handful of such immuno-therapeutics on the market, but now there are about 40. That’s the realm we want to take our research.
“We have the evidence to support the potential, but we have to move systematically. What I really hope to achieve is for people in UT’s College of Medicine to see potential collaboration.”
Academic partnerships are key to great research, he feels: “One of the reasons I accepted the position with UT is because now I’m also a 50 percent faculty member of the new School of Green Chemistry and Engineering. What I find especially exciting about its mission is the emphasis on interdisciplinary collaboration. This will be the first time, for instance, my group and I will work with chemical engineers.
“I’m looking forward to many opportunities like that in the foreseeable future.”