City of Hope researcher moves in on leukemia's ‘neighborhood’

 

A naturally curious child, she'd always been attracted to research, “searching for something” — the more complex, the better. She flirted briefly with paleontology as a possible career (because what kid doesn't like dinosaurs?).

 

Then her eighth-grade teacher gave a lesson about DNA.

 

“I loved it!” she recalled.

 

Growing up in a middle-class community in northern Italy, Carlesso watched all of her friends do the predictable thing — get a diploma and go to work. She plotted a different path: medical school and a one-way ticket to the U.S. “I'd been thinking about it since middle school,” she said.

 

As a young doctor, Carlesso loved treating patients. Hematology, her chosen specialty, provided the complexity she craved. But she wanted to make a broader impact.

 

“I felt overwhelmed, powerless,” she recalled, “treating one patient at a time, unable to do enough for them, having only limited therapies available. I realized I needed to understand their diseases better.”

 

She said “it was that frustration that gave me the incentive to shift into research,” where she could potentially affect thousands of lives.

 

In the two decades since, Carlesso has established herself as one of the country's preeminent authorities, whose insights have fundamentally changed our thinking about the way leukemia works.

 

And it's hardly a surprise to the fellow Italian and professor who recruited her.

 

“She's a great thinker in many areas,” said Guido Marcucci, M.D., director of the Gehr Family Center for Leukemia Research. “She's original, clever, creative, passionate and persistent. She looks at every different angle. Plus, she's extremely friendly and a great team player. It's very easy to collaborate with her.”

 

But it wasn't all that easy to bring her to City of Hope.

 

“She was doing great and very settled” after 10 years in the academic environment of her previous position, Marcucci remembered. So he tapped into Carlesso's still-powerful love for patients, showing her how City of Hope's patient-centered, bench-to-bedside urgency could fulfill her in ways no university ever could.

 

She came aboard in 2016.

 

“This is a unique place,” she said. “So much of the research is clinically oriented. The clinicians and the researchers work together, share facilities, and look out for each other. And everyone is open and receptive to one another's ideas.”

 

Her ideas have opened some eyes.

 

Digging deep into the inner workings of leukemia, Carlesso has taken her research in three interrelated directions, all based on the belief that nothing about cancer happens in isolation.

As important as it may be to analyze the composition of cancer cells, it may be even more crucial to grasp what's going on around those cells, in their so-called “microenvironment.” Because, as it turns out, not only does a tumor affect its surrounding neighborhood, the neighborhood itself may be creating the very conditions that allow tumors to grow and spread.

 

“Cancer hijacks the cells around it,” said Carlesso, “forcing those healthy cells to serve the cancer cells.”

 

And that's why eradicating the tumor may not be enough.

 

“The microenvironment will harbor and protect a few cancer cells, leading to a relapse,” she said. “You must correct the microenvironment in addition to killing the cancer.”

 

Carlesso is gratified that more researchers are coming around to this line of thinking, yet she feels that current clinical approaches still continue to focus exclusively on destroying cancer cells while ignoring the “neighborhood.”

 

As she examined that neighborhood, Carlesso discovered unique properties in one condition that's almost always present.

For over 150 years, scientists have believed that inflammation and cancer cell growth were connected somehow. Many inflammation-related ailments, like gastritis, cirrhosis of the liver, pancreatitis, prostatitis and others can develop into cancer in their respective organs.

 

So it makes sense to better understand the mechanics of inflammation, which may go in more than one direction.

 

“Chronic inflammation, which is an immune response,” said Carlesso, “puts the cells around the cancer into a state of constant activity, which may actually make the tumor stronger. And cancer cells may create inflammation to protect and support themselves, to make a 'good soil' for the tumor, so to speak.

 

“So we must find ways to 'normalize' the cell and stop that process.”

 

Many factors help determine the growth and differentiation of cells, cancerous and otherwise. Carlesso and her team are focused on one that seems especially relevant.

Nearly every multicelled creature makes use of Notch signaling pathways. They play a major role in the regulation of embryonic development. Mammals have four different Notch receptors. Mutations in those receptors can lead to cancer, especially leukemia and lymphoma.

 

Carlesso believes aberrant Notch molecules play a role in controlling inflammation by making cells more reactive and susceptible to it. Her lab has successfully induced bone marrow inflammation by manipulating Notch. “It's just one piece” of the leukemia puzzle, she said, “but sometimes one piece can be very important.”

 

Also very important to Carlesso is her determination to beat the drums for basic research, a field that deserves more attention than it usually receives. She's a fierce advocate on behalf of her research colleagues (“I'm their tiger mom,” she said), and that sentiment carries over into private life. Married to fellow City of Hope researcher Angelo Cardoso, M.D., Ph.D., they've collaborated on a number of projects and papers.

 

Remember, she said, basic research is where it all begins — especially at City of Hope.

 

“All of the innovative therapies that City of Hope has developed that are in clinical trials now — such as islet transplantation for type 1 diabetes, CAR T cells and gene-modified therapies for cancer and other diseases — are based on basic scientists bending at their bench for years before these therapies come to fruition,” Carlesso said. “Basic research is so important, but it takes time. If we look at what the research scientists are doing in the lab now, we will have a glimpse of the treatments of the future.”

 

Thanks to people like Nadia Carlesso, there'll be plenty more where that came from.

 

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