The pathway to genetic repair

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.

Taniguchi joined the Human Biology and Public Health Sciences divisions last November, after having made significant discoveries about DNA repair while researching Fanconi anemia as a postdoctoral fellow in Dr. Alan D'Andrea's laboratory at the Dana-Farber Cancer Institute. 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 and his colleagues found the genes involved in Fanconi anemia are part of a "pathway" that includes BRCA1 and BRCA2, two of the best-known cancer genes in human cells. When either of the BRCA genes or any of those in the Fanconi pathway are defective, the result may be breast cancer, ovarian cancer, or other malignancies.

"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."

Taniguchi's bench-to-bedside research aims made him a good fit for the center, according to Dr. Barbara Trask, director of the Human Biology Division. "We are very happy that Toshi has joined our ranks. He has done elegant studies to learn how cells respond to DNA damage, and he has a strong interest in translating these discoveries into improved diagnosis and treatment of cancer," she said. "We expect Toshi's translational research program to yield important new insights in tumor biology and also lead to new biomarkers for early detection and improved strategies for cancer therapy."

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, and 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.

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 cells become able to withstand front-line chemotherapy agents like cisplatin 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.

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

Now ensconced in his own Hutchinson Building lab, 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 center scientists studying cancer susceptibility in the general population, Taniguchi sees no shortage of collaborative opportunities. He plans to team up with one such PHS investigator, 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.

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 center's reputation and atmosphere led Taniguchi to Seattle. "Even in Japan, Fred Hutchinson is very famous among hematologists because of the bone-marrow transplantation," he said. "The science here is great, and the atmosphere is informal. People tend to be focused on the science, not politics.

"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."