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Meet our Researchers-For Lavie, Father Knows Best

Arnon Lavie intended to follow in his father’s footsteps and join the world of international business. His father, Avi, had other ideas for his son.

Lavie, University of Illinois Cancer Center member and professor of biochemistry and molecular genetics at UIC, intended to pursue an MBA when his father made a suggestion. Becoming a businessman can wait, he said. Study something you have a passion for. If, after that, you still have an interest in business, pursue it then.

Heeding his father’s advice, Lavie studied chemistry in his native Israel. And he has never left science.

Lavie is a structural biologist who utilizes his expertise in engineering enzymes to reduce the dangerous side effects and improve the safety profile of cancer therapeutics. Since he was a young scientist, Lavie was fascinated with understanding biologically relevant proteins on the molecular level – understanding how these nano-machines work – and intrigued whether he could use this understanding to engineer new or altered functions.

“Most scientists using mutagenesis as a tool either obtain no effect, or enzymes with reduced activity,” Lavie said.
“My goal is to obtain enzymes with increased activity using the structure as a blueprint for designing the mutations.”

One class of enzymes Lavie’s research team is focusing on is asparaginase, a chemotherapy drug that breaks down the amino acid asparagine, thereby eliminating cancer cells because they cannot produce protein. Asparaginase is predominantly used to treat acute lymphoblastic leukemia (ALL), the most common childhood cancer where white blood cells in the bone marrow develop errors in its DNA. It can invade the blood fairly quickly, and then spread to other parts of the body – lymph nodes, liver, spleen, central nervous system (brain and spinal cord) and testicles (in males).

Fewer than 6,000 new cases of ALL are diagnosed in the U.S. each year. Symptoms include fatigue, fever, loss of appetite or weight, enlarged lymph nodes, bone pain and bleeding from the gums. The disease can be fatal within a few months if not treated.

Asparaginase has been successful in treating ALL, but the drug also possesses a second activity – glutaminase – that has been linked with toxic side effects, such as pancreatitis, liver abnormality and coagulation problems, Lavie said. In prior research conducted in Lavie’s laboratory, Hien Anh Nguyen, PhD, discovered the required combination of mutations in this enzyme drug so that it could still hydrolyze asparagine but not glutamine. By crystallizing the drug Erwinase, an asparaginase used to treat ALL, in concert with either asparagine or glutamine, Nguyen discovered how they both specifically worked and identified sites on the proteins that could be modified.

In a new paper published in the journal Cancer Research, Nguyen reported the in vivo activity of this engineered drug. Nguyen’s research revealed that reducing the amount of glutaminase within asparaginase results in a drug that is highly effective against both T and B cell ALL, while reducing the toxicity.

 “We are engineering a greatly improved version of this drug (Erwinase) by eliminating the side activity, resulting in a significantly safer therapeutic that
will be able to treat patients previously unable to take this life-saving drug,” Lavie said.

“This is important, because this drug cannot be used in adults. It is predominantly used in pediatric patients, where the cure rates are 90 percent. But with adults, the cure rate is 40 percent. We may have a solution to using this drug more safely in adults because this population needs this,” he said.

Lavie, who obtained his PhD from Brandeis University in Waltham, Mass., and completed his post-doctoral training at the Max Plank Institute in Dortmund, Germany, and Nguyen, along with Amanda Schalk, PhD, and Ying Su, have founded a company, Enzyme by Design, to further develop their scientific discoveries.

“We don’t just want to save lives,” said Lavie, who has multiple patents and has licensed several of his innovations. “We want to maximize each person’s quality of life, especially when that person is in the battle of their life against cancer.”