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Killing Cancer

Former Vice President Joe Biden, champion of the $1.8 billion cancer “moonshot” named for his late son, told members of the American Association of Cancer Research in Washington, D.C., last spring that in the fight against cancer, a disease that “never surrenders,” the nation must be “unwilling to postpone, even for a second, to do all we can, for as long as it takes.”

John K. Buolamwini, BPharm, PhD, who attended the conference, has been doing battle with cancer for almost 30 years. He works to identify novel drug targets and discover compounds that can weaponize the body against an enemy that uses its host’s own cells, pathways and viral vectors to survive, multiply and kill.

“Cancer is a hydra-headed problem,” he said. “You think you have a handle on it, then something appears. It’s really a game of whacka-mole. You hit it in one place and it pops up in another.”

Dr. Buolamwini, professor and chair of pharmaceutical sciences in the College of Pharmacy, worked with an interdisciplinary team of scientists in discovering a new class of small molecule inhibitors of the rogue, cancer-causing protein MDM2, which opposes the effects of the famous tumor suppressor p53, a gene that is thought to regulate the cell cycle and stop damaged cells from dividing. The team identified a compound, SP141, which actually binds to MDM2 and causes it to degrade, followed by a cellular version of a garbage haul-away. Previous MDM2 inhibitors targeted the interaction between MDM2 and p53 and were found ineffective against cancers with mutated or deficient p53.

“It’s the difference between shackling the enemy and killing it,” said Dr. Buolamwini, who noted that the struggle to find inhibitors of MDM2 began in the early to mid-1990s.

SP141, as reported in the journal Gastroenterology in 2014, reduced levels of MDM2 in pancreatic cancer cell lines and inhibited the growth of pancreatic tumors in mice.

Another paper in the journal Nature Communications reported SP141’s ability to degrade MDM2 and delay breast cancer progression and reduce its metastasis. A still more recent paper reports that a series of compounds, including SP141, also works against breast and colon cancer.

Dr. Buolamwini was born and raised in Ghana, West Africa. He recalls impatiently waiting for his formal education to begin.

“I got a little school bag and told my father, ‘Take me to school!’ I earned scholarships and chemistry kept me going. I loved that you can create something new. I tell graduate students working on research projects, ‘If you make a new compound today, no one has ever made that compound before.’ We’re discovering something that we hope will have utility in disease, but we don’t really know what fate lies ahead of it.”

The new compound SP141 is just such a discovery.

“We didn’t know what it was going to do,” said Dr. Buolamwini, who collaborates on cancer drug development with a biologist at Texas Tech University. “We still don’t know where it’s going to end up. I find that exciting. My problem is not that I can’t make a compound, it’s which compound should I make?”

We've shown we can design compounds that can kill cancer and we can design compounds that treat Alzheimer's in mice. If we keep moving forward, the possible becomes real.
John K. Buolamwini, BPharm, PhD

Ninety percent of new drugs fail in the clinical trial phase, evidence, Dr. Buolamwini says, that “there’s still too much trial and error” in drug development.

“Drug discovery and development are very risky,” he said. “Companies are trying to balance risk and cost.”

He was an early adopter of computer-aided design (CAD) as a powerful tool for his molecular manipulations.

“I tell my students, ‘My career was made by CAD,’” he said. “I’m a medicinal chemist. I can make a compound if I really want to make it. But I need to know that I’m making a compound that could be useful as a drug.”

With this technology, he can model the molecular structure of the compounds bound together with MDM2.

“It’s very helpful to have a structural picture, because you know where things can fit,” he said. “If there’s a structure, I want to know it. If the FDA approves a drug, my first question is, ‘What’s the structure?’ I want to know what that compound looks like.”

SP141 still needs plenty of work before it can be considered for an investigational drug application.

“We’re still looking at how it gets into the tumors, how much is there, its toxicity,” Dr. Buolamwini said. “If those appear to be positive, we will apply to the FDA to begin clinical studies at phase 1, usually not to measure the drug’s effect, but to ascertain safety.”

Dr. Buolamwini’s lab also makes, modifies and tests compounds for the potential treatment of Alzheimer’s, heart disease and HIV/AIDS. He’s also investigating how to protect mitochondria from drug toxicity.

His deep commitment to and collaboration in front-end drug development, his books on novel cancer drug discovery, his dogged persistence — before electronic grant submissions, he once woke his two small children, put them in the car and drove to a FedEx many miles away to overnight a grant application by midnight — have contributed to molecular-targeted, lifesaving treatments for certain malignancies such as chronic myelogenous leukemia and lung cancer.

“My product is not a drug on the market per se, though I feel I have contributed to some of the drugs in the clinic,” Dr. Buolamwini said. “My product is information to fuel drug design, drug discovery, drug development. Companies study our publications to find out what is possible. We’ve shown we can design compounds that can kill cancer and we can design compounds that treat Alzheimer’s in mice. If we keep moving forward, the possible becomes real.”

This story first appeared in the Summer 2017 issue of Helix Magazine.

Posted September 20, 2017
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