Cancer Biology, Cell Biology
Fred Hutchinson Cancer Research Center
Dr. Taniguchi is also an assistant member of the Human Biology Division and the Public Health Sciences Division at Fred Hutchinson Cancer Research Center and an affiliate assistant professor of pathology at the University of Washington School of Medicine, Seattle.
As a physician in Tokyo, Toshiyasu Taniguchi treated many leukemia and lymphoma patients with DNA-damaging chemotherapy, only to watch the drugs lose their power as the tumors became resistant to the drugs. “I got really interested in how to improve treatment for those chemoresistant tumors and that motivated me to do research,” he says.
In Japan, it’s common for physicians to earn a Ph.D. after completing medical school and a clinical fellowship. Taniguchi continued seeing patients twice a week while he worked toward his research degree. But he was drawn to Boston because of its reputation for research excellence, and he completed a postdoctoral fellowship at the Dana-Farber Cancer Institute.
Now at the Fred Hutchinson Cancer Research Center, Taniguchi studies the role of DNA repair in drug resistance in cancer cells. He identified a repair pathway that is often inactivated in patients with breast and ovarian cancers as well in children with the predisposition to cancer known as Fanconi anemia (FA). He hopes to learn how to manipulate that pathway to resensitize cancer cells to chemotherapy.
While at Dana-Farber, Taniguchi helped identify several genes that are mutated or missing in children with FA. He showed that the normal forms of these genes make proteins that work together to repair damaged DNA. He also showed that they do it in concert with proteins encoded by two genes called BRCA1 and BRCA2—mutations in these two genes are known to increase susceptibility to breast and ovarian cancers.
Finally, he showed that the BRCA2 gene and an FA gene called FANCD1 are the same gene, linking one type of cancer susceptibility with another. “If the FA/BRCA pathway is defective, the cell cannot repair DNA and that will cause an accumulation of mutations,” Taniguchi says. “That promotes transformation of cells into cancer.”
But when the pathway is defective, it also makes the cancer cells vulnerable to chemotherapies that kill cells by damaging their DNA. The cancer cells can’t fix the damage caused by the drugs. Sometimes, however, cancer cells shake off that vulnerability. Platinum-based chemotherapy is very effective against some ovarian cancers—at first. But a few years later, the tumors come back and eventually become resistant to the original drugs.
At Dana-Farber, Taniguchi found the reason for the initial vulnerability. In some ovarian tumors, the FA/BRCA pathway is silenced by methylation, a process in which small molecules called methyl groups attach to a gene, preventing it from functioning. Methylation helps transform the cells into tumor cells, but it also makes them vulnerable to chemotherapy.
Over time, in some cancer cells, Taniguchi found that the methyl groups are somehow stripped away, reactivating the pathway and protecting the cells from chemotherapy.
When he started his own laboratory at Fred Hutchinson in 2004, Taniguchi continued his work with ovarian cancer, trying to discover other ways that resistance might arise. He found that, in tumors with an inherited mutation in BRCA2, no BRCA2 protein is made, leaving the tumor cells susceptible to chemotherapy. But when tumors recur in the same patient, Taniguchi showed, the BRCA2 gene is often repaired in the “new” tumor cells, so the FA/BRCA pathway is restored and the tumors are chemotherapy resistant.
Taniguchi is collaborating with clinical researchers to obtain chemotherapy-resistant tumor samples with BRCA2 genes that have been reactivated so he can further study the phenomenon and screen compounds in search of potential drugs that could inhibit the FA/BRCA pathway in resistant tumors and restore their vulnerability to chemotherapy.
His switch from medicine to research was a good idea, says Taniguchi. “Research scientist was actually my first career choice, and medical doctor was second. But I took my second choice first. I guess I thought that would be better, because it was more directly related to human happiness,” he says. He’s since realized that, by discovering how to treat a disease, one researcher can help many people. “Science can contribute to human happiness as well.”