Aydin Akyol

The Yale Cancer Center recently published a paper outlining the cause of one of the deadliest brain cancers.

In partnership with Gilead Sciences and researchers in Germany, Yale researchers identified what causes gliomas, or premalignant tumors, to transform into glioblastomas, which are malignant tumors. The team also identified a potential therapy to the lethal cancer. The study, which first began in 2013, was published in Nature Genetics on Nov. 30.

“We unbiasedly characterized the genetics of how premalignant gliomas become malignant and we identified in our laboratory a therapeutic approach,” said doctoral student Hanwen Bai GRD ’17.

The study focused on 41 patients who had premalignant tumors which, within 10 years, transformed into malignant ones, Bai explained. The genetics of both tumors were compared, and as a result, the researchers could directly understand the causes of malignancy. Four aspects were studied: gene mutation, large DNA fragment abnormality, gene expression and epigenetic changes — when external factors influence gene expression, in particular how DNA methylation of the tumor cells affected its progression. The study concluded that the four aspects contribute individually, but also “synergistically,” to cause the premalignant tumors to become malignant, and identified BET inhibitor — an anticancer drug — as a potential therapy for the cancer.

This was not the first study which attempted to analyze the cause of malignancy in gliomas, but it was the first to succeed in its purpose.

According to Bai, the Yale researchers’ work was able to build upon previous studies for two reasons, the first of which was the result of the sampling method.

“A lot of previous studies … have collected malignant and premalignant tumors from different patients, therefore they are comparing malignant tumors from patient A with premalignant tumors from patient B, and trying to understand the mechanisms underlying them,” Bai said. “Therefore that’s a very noisy comparison because different people have different genetic and epigenetic backgrounds so you’re kind of comparing apples and oranges.”

The Yale study avoided that mistake by analyzing 41 sets of tumors where the malignant and premalignant tumors were from the same patient.

The new study was also able to improve the depth and range of analysis in comparison to past studies, said Bai.

“A lot of previous studies, if and when they are indeed comparing tumors from the same individual, only look at one aspect of why the malignant transformation happened.” Bai said. “Whereas in our paper, for the first time, we comprehensively examined all four major aspects that could contribute to malignant transformation.”

Alexander Vortmeyer, professor of pathology and director of the neuropathology program at the Yale School of Medicine, explained that this advancement is especially important because of the deadliness of glioblastomas.

“Glioblastomas, you can say, are a total disaster,” Vortmeyer said. “It is not as frequent as, let’s say, lung cancer or colon cancer or breast cancer, but it’s not a rare disease. When you are hit with this diagnosis it is always a tragedy, because essentially there is almost nothing that can be done … The prognosis is about a year that you have to live.”

Furthermore, the current options for therapy provide very little in the way of extended lifespan. Vortmeyer noted that, in cases of glioblastomas, a patient will only get a couple of additional weeks to live with therapy.

According to Vortmeyer, there have been few if any advancements in the treatment of glioblastomas.

“The state of the art is horrible,” Vortmeyer said. “Essentially, people get these tumors today and they die from them a year or two later. The same thing happened 20 years ago, 50 years ago, 1000 years ago. Virtually no difference.”

The study will be highly influential in the field of cancer research for years to come, Vortmeyer said. By identifying BET inhibition as a potential therapeutic approach, there is now a strategy for finding a cure.

“BET proteins regulate gene expression of several known cancer genes by binding to upstream regions of those genes,” said Akdes Serin Harmanci, a research scientist in neurosurgery. “Small molecule BET inhibitors prevent binding of BET proteins and inhibit transcriptional activation of those cancer genes.”

Still, identifying a possible therapy is just the first of many hurdles. Bai likens this study to finishing up the swimming segment of a triathlon; currently, it is too soon to know if BET inhibition will be feasible in clinics, but it is a step in the right direction.

For now, according to Harmanci, further studies will be necessary in proving whether BET inhibitors are effective “in vivo” in gliomas.

In every 100,000 adults, two or three will be diagnosed with glioblastomas per year, according to the American Association of Neurological Surgeons.