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MU researcher's drug structure work might have implications for chemotherapy

Friday, December 28, 2012 | 6:00 a.m. CST; updated 11:08 a.m. CST, Friday, December 28, 2012
Mark W. Lee Jr., MU assistant professor of chemistry, and a team of MU medicinal chemists have created a more potent chemotherapy drug. By adding carboranes – clusters of boron, carbon and hydrogen – to the chemical structure of an existing drug, the chemists found the drug was better able to bind to cancerous cells. According to Lee, this tighter bond creates “a more potent mechanism for destroying the cancer cells.”

COLUMBIA — If you were to ask Mark Lee what he's working on these days,  he'd tell you he's trying to invent magic bullets.

Lee, an assistant professor and researcher at MU, and his colleagues are attempting to create a microscopic weapon that has one target: cancer cells.

Lee is the lead researcher on a team that unveiled in late August an experimental chemotherapy drug with a new structure that goes beyond organic chemistry and is potentially 10 times stronger.

Ten times might sound impressive on its own, but experimental chemotherapy drugs are far removed from the cancer drugs used today on patients. Lee said his team's drug is somewhere between a thousand and a million times more powerful than current chemotherapy drugs because the drug structure, called "carboranes," bonds more strongly a target within a cancer cell than current medications.

From here, the research goes in many directions. Lee hopes to combine the drugs his team has created with targeted cancer therapies to make them as advanced and effective as possible.

And though Lee's personal target is cancer, he believes the research he has done will help decrease side effects in medications for all maladies.

Because the drugs are too early in their development to be tested on humans, it's unknown if they will be declared safe. But Lee hopes the cumulative effect of his efforts to revolutionize chemotherapy will result in significantly fewer side effects, which would radically alter cancer treatments.

Magic bullets

Finding a cure for cancer through chemotherapy isn't like finding a flower with healing powers. It's more like weapon development.

Paul Ehlric, the Nobel Prize-winning scientist who developed chemotherapy in the late 1890s, first used the phrase "magic bullets." It refers to the fact that toxins will kill cancer cells but only if they don't kill the patient in the process.

Carl Freter, the director of the Division of Hematology and Medical Oncology at the MU School of Medicine, described the difference between untargeted and targeted therapies as the difference between a baseball bat and a silver bullet.

“Right now, we can kill all cancer cells, but that’s not the question," Lee said. "The question is, can we keep the patient alive while we’re doing it?”

Chemotherapy drugs currently use large amounts of medication to kill the cancer cells. Lee says the large quantity of the current drugs needed prevents them from being aimed properly, instead overflowing and attacking healthy tissues as well.  

Freter also explained that chemotherapy treatments developed in the past 30 years target cells that divide more quickly than others, which includes not only cancer cells but also cells such as hair and bone marrow. He said targeted therapies developed in the past 10 years target cancer cells directly, rather than other rapidly dividing cells.

Lee said drugs with a carborane structure are so effective that fewer chemotherapy molecules are needed and can be targeted more directly.

Lee has set his crosshairs on one precise part of the cancer cell.

His recent research has indicated that the enzyme Nampt plays a large part in creating energy for the cancer cells and their ability to heal themselves when damaged. Lee hopes the combination of the carborane structure, the recent developments in targeted therapies and the specific attention to the Nampt enzyme will be the magic bullet he has been seeking.

"I basically now consider myself an inventor, but my tools are molecules," Lee said. His interest in chemistry stemmed from his childhood wish to invent as an occupation. Now, he said, his work is similar to that of an engineer but with much smaller teams. On the carboranes, he worked with Yulia Sevryugina, Aslam Khan and Shui Ye.

"I wouldn’t be doing any other research if I were given the choice," Lee says of his work. "This is what my passion is." 

That passion and his interest in chemotherapy research came partly from his personal experience watching families deal with cancer.  He said watching his mother deal with the death of his grandmother showed him the effects cancer has on the survivors and made him want to make a contribution in the fight against cancer.

Carborane drug structures

What Lee discovered is that changing the structure of a chemotherapy drug by including a carborane will make it bond tighter to its target in a cancer cell.

Freter, described Lee's research as "extremely exciting." Because it re-examines the fundamental aspects of chemotherapy drugs, many are excited about its implications, he said.  

"Right now the medicinal chemist’s toolbox is limited to organic chemistry for the most part," Lee said. Carborane structures are inorganic compounds, and "at least in this particular case, carboranes were better than any of the purely organic groups we compared them with." 

A carborane molecule is a three-dimensional cluster of boron, carbon and hydrogen. When it bonds, a carborane molecule creates a unique, powerful hydrogen bond with a cell. Lee said this is the most powerful type of bond a drug can make with a molecule.  

Although carborane molecules are not currently used in any medications, Lee's research team isn't the first to use them in a a drug structure.  In 2004, Yasuyuki Endo, a researcher in Japan, discovered that the female hormone estradiol will still act as estradiol, even if the structure of the molecule is changed to include a carborane.

Lee said Endo's work played a large part in his decision to use carboranes to fight cancer.

“I’ll make a prediction," Lee said. "Within 10 years we will see all drugs made this way.”

The road ahead

Lee's work is gaining attention in the scientific community, far beyond MU.

The week the team's paper about carboranes was published, the American Chemical Society profiled Lee's research as one of the eight most significant papers during that week in its magazine, C&E News. The research was also highlighted in SciBX magazine. Lee says a few Web-based publications have also covered his work, and there are still more publications expressing interest.

Lee also is a former student and colleague of Frederick Hawthorne, director of MU's International Institute of Nano and Molecular Medicine. Hawthorne learned last week that he will receive a National Medal of Science for his research on the use of boron in experimental treatments for cancer, arthritis and other diseases.

Despite the interest, there is still a lot to be done before the chemotherapy drugs Lee has been developing will reach patients.

“I don’t want to give false hope; I don’t want to build hopes for current patients," Lee said. "It’s going to be a long time before this drug will come out."

Freter said that the FDA will most likely want to see more data on carborane-based drugs to be sure some of the problems currently seen with targeted therapies are resolved before they can be tested on humans.

Freter said that even with targeted therapies, areas of the body sometimes become unintended targets. Some side effects are not resolved by the targeted nature of the drug and can also be a problem.  

Another potential problem is the way the drug concentrates in the urine while being expelled from the body.

He described these issues as falling under the category "technical difficulties you always see in the small print."

"There are always technical difficulties when delivering targeted therapy to the body," he said.

Lee said it will take testing to know for sure if there are drawbacks in the carborane structure specifically. For now, he said he does not expect any.

“Yeah, I really believe this is going to happen," he said. "I don’t believe necessarily that we're going to cure all cancer this way, but I think we’ll see some revolutionary improvements over the next 10 years in targeted therapies.”

Lee estimates the drugs he has been developing could be available in about 10 years, if approved by the FDA.  He's always quick to add an "if."


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