Toshi Taniguchi aims to translate his fundamental studies on how the body repairs DNA to better cancer diagnosis and treatment

By COLLEEN STEELQUIST

Dr. Toshi Taniguchi hopes his studies of the body's DNA-repair mechanisms will eventually help cancer patients.

When people talk about a one in a million chance, it's usually to describe a rare opportunity. Sometimes it means just the opposite — a singular, devastating blow. Such is the case with Fanconi anemia, a seldom-seen inherited condition that places children at risk for bone-marrow failure early in life and various forms of cancer as they get older. Many patients don't live past young adulthood.

Dr. Toshiyasu "Toshi" Taniguchi, a biologist and physician who specializes in blood diseases, believes studying rare genetic diseases with cancer susceptibility like Fanconi anemia is a productive way to gain insight into the origin and development of cancer in the general population.

The Hutchinson Center recently recruited Taniguchi to join its faculty, after he made significant discoveries about DNA repair while researching Fanconi anemia as a postdoctoral fellow at Dana-Farber Cancer Institute in Boston. His work provided new insight into the connection between the body's ability to repair damaged DNA and cancer. Since DNA is the genetic blueprint, any mistakes can be disastrous for health.

Taniguchi's studies of genes — the fundamental units that determine human hereditary traits — are prime examples of the basic biological research that build the foundation for breakthrough medical treatments. He aims eventually to translate his discoveries into improved diagnosis and treatment for cancer patients.

Studying a genetic pathway

Taniguchi and his colleagues found the genes involved in Fanconi anemia are part of a pathway that includes two of the best-known cancer genes: BRCA1 and BRCA2. When either of these genes or others in the Fanconi pathway are defective, the result may be breast cancer, ovarian cancer or other malignancies.

Fanconi anemia is caused by a defect in the body's natural DNA-repair mechanism. The genes associated with the disease are part of a suite of "caretaker" genes that protect the body against cancer. The failure of one of these genes causes the bone-marrow cells to die; it also predisposes patients to cancer because the body can't repair cancerous mutations. A bone-marrow transplant is the only long-term cure, but even if the anemia is cured, these patients often develop other cancers later.

"Understanding how DNA is repaired is important to cancer biology," Taniguchi said. "Your DNA can be easily damaged by a lot of things, so the mechanism for repairing that damage is really important. The pathway I'm studying is one of the mechanisms for repairing DNA."

DNA repair also turns out to be important for explaining why some chemotherapy regimens fail over time. Taniguchi has studied how the Fanconi-BRCA pathway is involved in drug resistance in ovarian-cancer cells to better understand how tumor ells become able to withstand chemotherapy agents that had once caused them to shrink. He found that cancer cells are capable of doing a genetic about-face — through a process called gene silencing — reversing the very abnormalities that once made them vulnerable to chemotherapy.

Drug resistance is a major complication in cancer chemotherapy and accounts for the failure of chemotherapy to cure the majority of cancer patients. With further research, he hopes to determine new strategies for preventing drug resistance.

"If we can find a correlation between drug sensitivity and the defects of this pathway, we could predict the outcome of chemotherapy in patients and customize our approach," Taniguchi said. "We may also be able to use drugs to inhibit the Fanconi-BRCA pathway so even a drug-resistant tumor could be made sensitive again with treatment."

Driving medical progress

Taniguchi was drawn to research after several years of working as a hematologist in his native Tokyo. "I felt some limitations with the current state of medicine, so I really wanted to do something that could progress medicine," he said of his decision to switch from an exclusively clinical career. However, his years of patient care were not wasted. "That type of background makes me welcome projects that are important for both basic science and clinical applications," he said.

The Hutchinson Center's reputation and atmosphere led Taniguchi to Seattle. "Even in Japan, the Hutchinson Center is very famous among hematologists because of the bone-marrow transplantation," he said.

Now ensconced in his new laboratory, Taniguchi is eager to continue his work with the Fanconi-BRCA pathway. "Right now, I'm focused on that pathway only, but in the future I want to broaden my interests into DNA damage response and DNA repair itself," he said. "There's a lot of potential there."

With numerous Hutchinson Center scientists studying cancer susceptibility in the general population, Taniguchi sees no shortage of collaborative opportunities. He plans to team up with Dr. Nicole Urban, who is working to improve clinical outcomes in patients with reproductive and other cancers. Taniguchi believes Urban's ovarian-cancer registry will prove useful for testing his hypotheses about the Fanconi-BRCA pathway.

"The science here is great, and the atmosphere is informal. People tend to be focused on the science, not politics," he said. "The diversity of the science here excites me. There are lots of people working on very different things. That will stimulate my scientific thoughts." For Taniguchi, research is more than a job; it's his passion. When asked what he does for fun, he replied with a grin, "Other than science? Science itself is, of course, fun."

David and Pamela Johnston.

Why we support fundamental research

"As children, we thought that scientists just discovered things, like finding a seashell while walking on the beach. As adults, we better understand that hard work, thorough planning and resources are needed. We also misunderstood how much was known about how our bodies work. Who knew we had so many and such complicated parts that could cause us trouble? Before we understand how our bodies work, how can safe ways be found to help us? Moreover, once how something works is known and shared, the uses of that knowledge extend beyond the reason that the initial question was asked. These are reasons that we support fundamental science research at the Hutchinson Center."

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