Chemotherapy-resistant cancer may be treatable, study shows

New treatment opportunities for uterine serous carcinoma (USC) — a highly aggressive, chemotherapy-resistant form of endometrial cancer — could soon be discovered as a result of recent findings produced by a yearlong Yale study.

A collaborative 34-member team of Yale scientists, including researchers specializing in gynecological cancer, genetics, pharmacology and biostatistics, studied the tumors of 57 female patients suffering from USC to determine the molecular basis of the tumors’ aggressive behavior. After surgically removing the tumors from the patients, the researchers sequenced each tumor’s genes to find specific mutations critical for these tumors’ development and detected three specific genes frequently mutated in patients suffering from USC. The team’s results were published in the Jan. 28 online edition of the academic journal Proceedings of the National Academy of Sciences.

“We have been able to identify potential molecular pathways that are important to the development of these cancer tumors,” said Yale School of Medicine professor of obstetrics, gynecology and reproductive sciences Alessandro Santin, senior author of the study. “We have opened an avenue for new therapy for this disease, because we now have something to target, which was previously unknown.” He explained that the research team looked for multiple mutations in specific genes to see which genes were causing the tumors.

“What we have done is extracted DNA from the tumor cells using exome [gene-encoding proteins] sequencing,” Santin said. “Most of the genetic mutations that cause cancer take place in these genes that encode proteins — not 100 percent, but between 85 percent and 90 percent. We looked through all of the 21,000 genes to look for recurring mutations present in specific genes.”

The most biologically aggressive subtype of endometrial cancer, USC is only found in 10 percent of all individuals with endometrial cancer. However, USC tumors are incredibly dangerous because of their resistance to standard treatments and their ability to move quickly to an individual’s abdominal cavity. In fact, this cancer typically results in between 4,000 and 5,000 deaths each year and accounts for 50 percent of all deaths for endometrial cancer victims, according to the study.

Chair of genetics at Yale Richard P. Lifton, a corresponding author of the study, said the study’s results could lead to new discoveries to help individual patient cases, according to a Jan. 28 Yale News release.

“These new findings define the biological basis of this cancer and suggest new opportunities for personalized therapy,” Lifton said.

Now that researchers have a better idea of the tumor’s biology and the mutations causing USC, they can target therapies to address these genetic mutations. Moving forward, Santin said the goal is either to take advantage immediately of FDA-approved drugs used for similar mutations in other tumors or to start from scratch and begin new therapy based on the specific genes they found in these tumors. Until the research was produced, doctors did not know the most effective drugs to use to treat this cancer, Santin said.

“Now that this has been reported to the scientific community, the point is to make clinics aware to treat patients using this new knowledge,” he said. “We are trying to improve the quality of care and the knowledge base that we can provide to our patients when they develop this devastating USC cancer.”

Gilead Sciences Inc., an American biotechnology company that collaborates with Yale, helped support the cost of gene sequencing during the study.

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