A younger Stacy L. Cooper, MD, had no idea she would one day be honored as a Sohn Fellow working at the preeminent Johns Hopkins School of Medicine, Baltimore, and juggling clinical care while developing novel therapies for acute myeloid leukemia (AML).
Cooper, Assistant Professor in Pediatric Oncology at Johns Hopkins Children's Center, grew up as a rough-and-tumble, outdoorsy kid in her native upstate New York. "I didn't have anyone who was 'medical' in my family at all. I had no exposure to medicine. In fact, I went to college at the University of Notre Dame intending to become a biology teacher," she explained.
Then suddenly, everything changed.
"One summer, I was waiting tables at night, and trying to figure out my future by day. So I cold-called various professional people to see if they would allow me to spend time with them to see what their jobs were like," Cooper recalled, laughing at her youthful moxie. "I was very fortunate to have a lot of people say yes to my crazy requests."
She subsequently spent a week at a pharmaceutical company, time with a biology professor, and even followed a primary pediatrician. But it wasn't until "that one day" when she shadowed a surgeon that an alarm went off in her head.
"I spent one day with a vascular surgeon and I thought it was the coolest thing I had ever seen in my entire life. I knew right then I had to go into medicine," she recalled. "What was it about that particular day? I've thought about it a lot; it is seared into my neurons. That doctor was so thrilled about what he did. He wanted to share that excitement and went out of his way to allow me to be involved. He generously showed me really interesting aspects of his work. I learned from him immediately the importance of being cognizant of the people who are coming up through training and the effect you can have by sharing your passion. Everything became crystal clear that one day. I went home and told everybody, 'I am going to make some changes. I am going to medical school!'"
Going All-In
Cooper made good on that declaration. She spent her next summers working with that doctor while completing undergraduate work. Under his influence, she decided to become a surgeon, but once in medical school at Syracuse University, Syracuse, N.Y., a rotation in pediatrics and later pediatric oncology further defined her evolving career path. Pediatric oncology supplanted vascular surgery as the new "... coolest thing I'd ever seen."
"My attraction was twofold," said Cooper. "First, I liked the longitudinal relationships pediatric oncologists had with patients and their families. In contrast, I have many friends who are emergency medicine physicians and whose work I really respect, but there is no way I could do that-treat a patient, see them walk out, and never see them again. I like forming a relationship with patients and really getting to know them. Second, I liked the fact that these are really sick patients for whom you can often make a difference with their therapy. A lot of pediatric cancers are very treatable; it is a hopeful area of medicine."
Cooper came to Johns Hopkins for post-graduate training, a residency, and later fellowship training. "I've been fortunate to be able to stay on. It is one of the best possible institutions-I know it sounds so cheesy, but it is really true. I am surrounded by people who are really inquisitive and great teammates. This makes everything else so much more rewarding."
Research Focus
Though she loves the hopefulness of pediatric oncology, it is for patients whose hope is greatly curtailed that Cooper dedicates much of her research activities. Working in the lab of Alan D. Friedman, MD, her work focuses on developing novel therapies for AML, which has an approximately 50 percent mortality rate. "AML is a very aggressive leukemia," Cooper lamented, "and the rate of complications from its therapy and its incidence of relapse make it especially terrible. Clearly, we need some innovations in therapy compared to current conventional chemotherapy."
Hoping to help combat those realities of AML, Cooper is examining some of the mechanisms that cause this cancer. One approach, she said, is to look at how normal white blood cells develop and then determine what aberrations may occur and what mechanisms are implicated in the formation of AML.
Cooper focuses on C/EBP-alpha, a protein that is decreased in more than half of all AML patients. By determining how the production of this protein is regulated, she aims to understand the mechanisms for its reduction in leukemia and develop strategies to target C/EBP-alpha as a novel therapy for AML.
"C/EBP-alpha is a protein that is critical for normal white blood cell [myeloid] development," she detailed. "We have found it is decreased or down-regulated in the majority of cases of AML. This decrease seems to be the common pathway for many cases of AML. We are trying to determine why C/EBP-alpha is decreased in these cases and exactly how that happens. Then, ideally, we hope to find ways of increasing the levels of C/EBP-alpha, which would be a form of differentiation therapy."
Asked if once the missing protein is supplied, the cell might normalize, Cooper answered, "That is the hope, exactly. We want to get the cell back on a normal path of development."
An Assist From CRISPR
Cooper further explained that she and her team are specifically looking at a small piece of DNA in the gene that encodes C/EBP-alpha. (Friedman's lab had previously identified C/EBP-alpha +37kb enhancer, a region in the DNA which determines how much of that protein is made.)
"Our hypothesis is that there are cases in which the enhancer is either mutated or otherwise affected so that it makes less C/EBP-alpha than it should. My initial project showed the transcription factors that bind to and activate the enhancer," Cooper explained. "The next step was really interesting. We took advantage of CRISPR technology-a game-changing editing technology available to all of us now. We created a mutated enhancer and mutated the ETS [a family of transcription factors unique to animals] sites that we thought were important. We replaced normal enhancer with this mutated enhancer in a cell line that would grow and divide.
"From there, we could actually see what the consequences of having that mutated enhancer in a real cell are." The findings were as Cooper expected. "We found a marked decrease in C/EBP-alpha in the cells that had mutated ETS sites. We previously hadn't known that before."
Now Cooper's team is starting to look at the changes to the epigenetics-to the histone modifications-in the cells with the mutated enhancers. "We can use these cells to look at the changes in chromatin that tell an enhancer to be activated," said Cooper. "We see that, in the mutated enhancer, those histone marks are decreased; there is less activation of the enhancer."
Asked if a reactivated enhancer could turn the problem around, Cooper said, "The answer, in theory, is 'maybe ... someday.' Our work isn't at that point yet. We still need to hammer out more details on how the enhancer is regulated before we can determine how to approach repairing an injured enhancer. And there are a lot of caveats; there could be many downstream consequences to these types of complicated pathways. We really need to make sure we understand it from all angles so we don't cause harm."
Cooper's work continues with what she called "a ton of support from my institution and my mentor [Friedman], and from two foundations that have been very supportive-Alex's Lemonade Stand and the Damon Runyon-Sohn Foundation. I can't say enough about how important it is to have protected time to do research. Support has given me that precious time to balance research with the clinical care. And it has also helped me to clear what is often the biggest hurdle of all-funding."
Moving Forward
In considering her short- and long-term goals, Cooper said, "In the shorter term, I will continue to tease apart how this enhancer is regulated in AML. The next trajectory will be taking what we now know about the enhancer and applying it to primary human samples-banked samples of human leukemia cells-and studying the enhancer in them.
"In that way, we are taking a little bit of a pivot into what some people call the more translational realm of actual human samples; this is necessary to have a therapeutic effect. If our findings translate to humans, that will take us to long-term goals, which for me would be making meaningful gains in the survival of children with leukemia and finding innovative ways of targeting leukemia in patients who currently have poor survival."
The ultimate success, said Cooper, would not only be life-extending therapies, but curative ones. "Finding a cure for pediatric cancer is the ultimate goal," she said without hesitation. "Saving a young life is special to me in that it preserves a potential for maybe 70, 80, or more years of productive life. It is such an honor to form relationships with young patients and their parents, and to help through research is a true privilege.
"This is an exciting time to be a pediatric oncologist in terms of the new frontiers of immunotherapy, targeted therapy, and a shift away from conventional chemotherapy," Cooper added thoughtfully. "Now we not only hope to increase the rate of cure, but to do it with less toxicity as well, which is particularly important for children who have longer to deal with side effects. At last we have some very real potential to cure diseases without exacting as much toll on patients' bodies as before. All of the fields are coming together, and it is very exciting."
At day's end, Cooper is likely to revert to the status of that kid from upstate New York. "I still love outdoor activities-like hiking and cycling," she said, having recently completed a 100-mile bike ride and a hiking trip to Wyoming. "It's a matter of getting unplugged from everything, blowing off some steam, and clearing my head. It is where I do my best thinking about everything-including work. I mentally troubleshoot things for research projects and piece things together when I am hiking or riding. And when I am pedaling up a tough hill, concentrating on work helps me take my mind off that climb. It works both ways," she said with a small laugh and plenty of good humor.
Valerie Neff Newitt is a contributing writer.
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