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Dr. Charles Kaufman’s patients are always a little taken with the zebrafish. Kaufman is a physician-scientist who treats patients at Siteman Cancer Center. He is also an assistant professor of medicine and developmental biology at Washington University and studies melanoma in his lab. In photos on the lab’s website, he and his researchers pose with stuffed animal versions of the fish. Instead of its metallic blue stripes, the stuffie version has blue flowers. Kaufman’s lab uses the zebrafish—the real ones, 1-inch-long aquatic wonders that share more than 70 percent of their genes with humans—to study melanoma. Specifically, Kaufman’s lab members want to figure out what mechanisms control the cancer’s onset. They’re attempting to identify the start of the disease very early in order to treat it before it spreads. Skin cancers are the most common cancer, and, according to the American Cancer Society, even though melanoma only accounts for 1 percent of skin cancer, it makes up the majority of skin cancer deaths. An estimated 7,180 people will die of melanoma this year.
At the end of 2019, cancer research was at a peak, notes the journal Future Oncology. There was a “tsunami” of targeted therapies and thousands of clinical trials evaluating various cancer drugs. The COVID-19 pandemic changed everything. Quarantine and mitigation efforts affected cancer researchers, and health care systems’ main focus has been caring for COVID patients. “Suddenly, we saw a shift in priority levels where the fight against SARS-CoV-2 infection has become more urgent and crucial than the fight against cancer. As a result, cancer research has slowed considerably,” write Hampig Raphael Kourie, Roland Eid, Fady Haddad, Marwan Ghosn, and Dolla Karam Sarkis in the journal article, titled “The future of cancer research after COVID-19 pandemic: recession?”
But at a time when cancer research experienced a setback, Kaufman’s lab recently applied to and received one of the larger National Institutes of Health awards for its work. That work might not have been possible without an earlier award from the Cancer Research Foundation, an organization based in Chicago that acts like a startup incubator or accelerator for cancer research. The CRF infuses early-career scientists (indeed, Kaufman is only 45 years old—he was 40 at the time of the CRF award) and their labs with money to conduct ambitious research. It bills itself as a group of “cancer research venture philanthropists.”
The CRF has traditionally worked with the University of Chicago and Northwestern University, which have comprehensive cancer centers. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine is also a comprehensive cancer center, and the CRF has awarded researchers here, too. And it might be increasing its presence in St. Louis with Mark Mantovani having recently joined the CRF’s board, its first member from St. Louis.
Big Challenges, Big Ideas
“I have a book inside me about thinking outside the box,” starts Mantovani. The former chairman, president, and CEO of Ansira most recently ran for St. Louis county executive in 2020, on a promise to innovate and experiment. Mantovani signed on as CRF’s newest board member because he was attracted to working with cancer researchers who were thinking outside the box.
“I think that great achievements are typically the product of people who are thinking differently, and learning how to be supportive of that is important,” Mantovani says. Both he and his wife are also cancer survivors.
The CRF has given “seed capital” to 180 researchers, to “launch their ideas in the fight against cancer.” The organization was founded in 1954 by Maurice Goldblatt, co-founder of the eponymous department store chain, in memory of his brother. Twelve years after the CRF was launched, Dr. Charles Huggins, one of its earliest grantees, won the Nobel Prize in Medicine for his discoveries concerning hormonal treatment of prostatic cancer.
Kaufman received his CRF award in 2016. He was a student at Wash. U. in the 1990s and then moved to Boston for his residency, working at the Dana-Farber/Boston Children’s Hospital. But for the research component of his hematology and oncology fellowship program, he wound up in the lab of Dr. Leonard Zon.
Kaufman wanted to better understand why cells behave the way they do. He wasn’t looking to work in melanoma research—though his Ph.D. was in skin biology—but Zon’s lab was working on a melanoma project. Kaufman set out to understand why a melanoma cell behaves the way it does—and whether he could make it act like a normal pigment cell.
Enter the zebrafish. Kaufman developed a fish that, upon the formation of a melanoma cell, switches on a glowing green color. The green illuminates the melanoma cell, and that allows Kaufman to track the first cells of the tumor. That green biomarker is actually green fluorescent protein (GFP), which is found in jellyfish. (The scientist and researchers who discovered it and its application as a marker won the 2008 Nobel Prize in Chemistry.)
“It sounds like an obvious thing,” Kaufman says, “but it’s actually really hard to do. We can track tumors when they’re big, bulky, and millions of cells, but when you want to find the first cell, that’s difficult.” It took him two years to develop the fish that could emit the green beacon.
Another postdoc developed the zebrafish with melanoma. More than half of human melanomas have a mutation called BRAF. That gene is transferred to the fish—and the fish gets the cancer, first developing moles and then tumors.
Now that Kaufman’s team can see these cells, they can see what other changes that are expressed in genes occur in the zebrafish at the same time. Knowing these changes could have applications in both melanoma detection and prevention. Kaufman’s lab hasn’t applied this yet, but knowing what other changes are present with melanoma could allow doctors to perform liquid biopsies. That blood test would look for a signature for these mutant genes or other factors that would indicate that a cell is “behaving poorly,” Kaufman says.
As far as prevention, Kaufman explains, there are lots of potentially bad mutations that happen in normal cells that thankfully don’t develop into cancer—the key is preventing the switch in the ones that do. For people with a family history of melanoma, those who are exposed to the sun often, or those who have prior melanomas, there are chemicals that can modulate that gene expression—“that can tamp down that tendency for the bad cell to come out,” Kaufman explains.
It sounds complicated and bold—but also logical. That begs the question: Why would research like Kaufman’s need funding from the Cancer Research Foundation, which states that it steps in where “financial support is needed most”?
The reason is the way that grants for cancer research typically work. The largest pot of funding comes from the National Institutes of Health. But those grants traditionally require researchers to present preliminary data—which means they need money to research and obtain that data, which necessitates a lab that’s what Kaufman calls a “functional enterprise.” They need more than just a good idea.
“What’s great about places like the CRF is that they take a little bit more of a view that’s like, ‘We think you have a good idea, so go with it,’” Kaufman says. “That money, as a young investigator, allowed us to generate a good amount of that preliminary data. The Cancer Research Foundation liked what we were suggesting, and then we got that award, and that allowed us to do this characterization of these early green cells in the melanoma fish. With that research, we applied and recently got one of the larger NIH awards.”
What’s particularly interesting about the Cancer Research Foundation funding in Kaufman’s case is that in the process of his research, the lab noticed something interesting that it didn’t expect to find.
In performing the studies in the lab, Kaufman noticed that the zebrafish in St. Louis were getting melanoma faster than the ones he had worked with in Boston and that feeding might be the issue. Now he had the opportunity to rigorously test what happened when the fish were fed a more measured diet. The tumors appeared more slowly. Now, thanks to that initial funding, Kaufman’s lab has an entirely new set of preliminary data that will help them branch off and study more about how nutrition and metabolism could be affecting melanoma. Kaufman says that one of the most common questions he hears from patients is whether they can alter anything in their diets to affect their skin health.
While wrapping up our conversation, Kaufman reflects on his time at Wash. U. and Siteman. “Not that there aren’t other medical centers like this in the country, but I was excited to come here [because of the] combination of a really active clinical research group and the amount of basic science with animals and cells,” he says. “It gives us a lot of opportunities, when we get to that point, to think of how we bring this to patients and have the infrastructure around us to do that.
“I think that's sort of a special aspect of the place.”
