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Desire to discover hidden pathways motivates cancer researcher

Aug. 14, 2014

A practicing-oncologist-turned-cancer-researcher, Nadia Carlesso, M.D., Ph.D., has traveled from bedside to bench -- and from Italy to Indiana -- pursuing a desire to unravel the mysteries of a disease whose causes can remain frustratingly hidden from view.

As a scientist, Dr. Carlesso studies the biochemical and genetic pathways that give rise to new blood cells in the bone marrow. The ability to understand these pathways is the key to identifying the "wrong turns" that lead to myeloproliferative neoplasms, or MPNs, a group of diseases involving white or red blood cell overproduction that can develop into cancers such as leukemia. She is particularly interested in the role of four receptor proteins involved in to cell-to-cell communications -- the notch-signaling pathway -- as it relates to the formation of new blood cells.

Nadia Carlesso

The Carlesso Lab. Back row, left to right: Amy Zollman, imaging technologist; Liyun Cao, Ph.D., postdoctoral fellow; and Huajia Zhang, doctoral student. Front row: Lin Wang, Ph.D., postdoctoral fellow; Nadia Carlesso, M.D., Ph.D., associate professor of pediatrics and medical and molecular genetics; and Sonia Rodriguez, Ph.D., assistant professor of pediatrics. | PHOTO BY ERIC SCHOCH

"We're trying to understand how (these pathways) function because when you understand how things should work, you can also understand how they can go wrong," said Dr. Carlesso, who is an associate professor in the Departments of Pediatrics and of Medical and Molecular Genetics at the IU School of Medicine. "As a physician in hematology/oncology, you really want to understand the correct processes so you can pinpoint, and then intervene, precisely where things start to go wrong."

Dr. Carlesso is also a member of the Indiana University Melvin and Bren Simon Cancer Center and the Herman B Wells Center for Pediatric Research.

Her research breaks down into three major areas: blood cell regulation during sepsis, the notch-signaling pathway and MPNs. But despite these three separate topics, the research remains closely interrelated. Most recently, Dr. Carlesso published an article in Cell Stem Cell on a study finding low levels of notch signaling appear to cause elevated levels inflammation within the bone marrow, leading to the development of MPNs. The conclusions are particularly complex since elevated notch signaling has also been implicated in cancer development -- and is frequently targeted in cancer treatments.

"Not all diseases are clear cut; they don't all have one major gene alteration causing every symptom," Dr. Carlesso said. "MPNs develop from a lot of different mutations, making them very complex and difficult to target. Or if you can identify and block a target, it's not always sufficient to bring the patient into remission. Indeed, despite their heterogeneity, all these diseases have in common an inflammatory state."

Dr. Carlesso’s research suggests physicians treating MPNs may need to consider targeting not only the specific mutations that are found in the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation.

"We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation into acute leukemias," she said.

About 176,000 people in the United States are currently diagnosed with MPNs, for which there is no proven effective therapy. Dr. Carlesso, who started treating patients with the disease as a physician in Italy, cited frustration over a lack of treatment options as an important motivator in her decision to return to school for a Ph.D., shifting her efforts toward lab work to unravel the causes underlying the disease.

"It was a hard decision, but I felt I had to do a Ph.D.; it was too difficult to balance seeing patients and going as deeply into the research as I felt that I needed," she said. "As a doctor, I'm most satisfied by completing a difficult diagnosis and seeing my patients respond well to therapy. As a scientist, I get the most reward from solving a mystery, or getting closer to its solution. It's the passion of knowing my effort to understand a disease is linked to helping people."

Dr. Carlesso's Ph.D. in experimental hematology was conducted at the Dana-Farber Cancer Research Institute in Boston under James Griffin, a physician-scientist who performed pioneering work on the molecular role of the "Philadelphia chromosome" in chronic myelogenous leukemia, or CML.

"I wanted to go to the States because of the incredible labs and opportunities available to delve into a subject," said Dr. Carlesso, whose Ph.D. program was based at the University of Genoa in Italy. In addition to her advanced degrees, she also holds a diploma in classical studies from the Liceo M. D’Azeglio in Turin, Italy, where she studied Greek and Latin, philosophy and history.

After departing Boston, Dr. Carlesso joined IU in 2006. In addition to overseeing a research lab at the Wells Center, she remains active in teaching and learning as the director of the Student Research Program in Academic Medicine, which provides first- and second-year medical students the chance to work in a lab for the summer. Dr. Carlesso revived the program, whose nearly 30-year history had come to end in the early 2000s, after joining the school.

"This is a really unique program -- not a lot of other universities have anything like it -- but we really had to rebuild everything from scratch," she said. "It’s very important that our students get the chance to do first-hand research; they might find out that it’s not the thing for them, or they might find out that they really love it and want to embrace academic medicine as a career."

Based upon the first two successful years, as well as historical data from the original program, Dr. Carlesso earned a National Research Service Award from the National Institutes of Health to continue the program in 2008. The Student Research Program in Academic Medicine is also supported in part by the Indiana Clinical and Translational Sciences Institute.

In addition to an enduring passion for research, Dr. Carlesso gained another lifelong companion as a doctoral student: her husband, Angelo Cardoso, M.D., Ph.D., who was serving a fellowship at Dana Farber. Today, Dr. Cardoso is also a member of the IU Simon Cancer Center and Wells Center, as well as adjunct assistant professor of pediatrics at the IU School of Medicine. His research also involves advancing knowledge on the role of microenvironment in leukemia progression.

"It's a good thing having a person in your life who does the same things you do; who understands your challenges -- why you work long hours, why you're working the weekends," she said. "We've done projects together and have proposed grants together.

"We talk about science a lot," she said with a laugh.

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