Twenty years after his initial discovery, a UBC scientist paved the way for a new cancer drug

For Dr. Poul Sorensen, the path to notoriety began with a seemingly niche discovery.

Twenty years ago, Sorensen — a professor in the UBC department of pathology and laboratory medicine — had just returned to Vancouver from Los Angeles, where he had been working as a postdoctoral fellow at the University of Southern California. He set up a lab at BC Children’s Hospital and began studying chromosomal translocations and their effect on pediatric cancers. Chromosomal translocation describes a process by which chromosomes — carriers of genetic information — are rearranged, “trading” pieces with other chromosomes.

Sorensen knew that these chromosomal translocations could play a role in cancer development, but he was particularly intrigued by a rare type of pediatric cancer called congenital fibrasarcoma which affects connective tissues. What drew him to the study of this specific cancer was the fact that, with the diagnostic tools of the time, it was nearly impossible to distinguish cancerous growths of that type from benign growths on connective tissues called fibromatosis.

“If you just looked down the microscope, you couldn’t tell them apart,” he said. “They really looked the same.”

So he and his team turned to the molecular differences between the tumors in their search for a reliable diagnostic marker for fibrasarcoma. Sorensen had noticed a chromosomal change associated with the cancerous tumors and upon further investigation, they discovered it was the result of chromosomal translocation.

At this point, Sorensen tasked one of his PhD students at the time, Stevan Knezevich, with identifying the specific details of the change. One genetic change that can occur as a result of chromosomal translocation is gene fusion, where separate genes come together to make a new gene. Knezevich eventually identified a specific gene fusion associated with congenital fibrasarcoma that resulted in a new gene called ETV6-NTRK3.

When the team published these results in 1998, they were of interest to pediatric oncologists concerned about finding an improved diagnostic marker for fibrasarcoma, but otherwise went largely unnoticed. “Even though it was potentially drug-able, it’s so rare that no pharma company was going to go after it,” said Sorensen.

Once his team had identified the fusion mutation ETV6-NTRK3 as the source of the cancer, they turned their attention to understanding the exact mechanism by which the mutation caused cancers. What they found was that the mutation produced a mutant enzyme that plays a role in cell growth and does not need a chemical trigger to be activated. This, in turn, leads to the uncontrolled cell growth that characterizes cancer.

After discovering the particular mechanism that made the fusion mutation cancerous, something unexpected began to happen. The ETV6-NTRK3 mutation that Sorensen and his team had identified in 1998 as specific to congenital fibrasarcoma began to show up in connection with other cancers as well.

Soon after their initial discovery, Sorensen and his team detected the mutation’s presence in a significant number of breast cancer biopsies. Sorensen would go on to partner with Dr. Stuart Orkin — a pediatric oncologist at Harvard Medical School — to demonstrate in a 2007 paper that the ETV6-NTRK3 mutation was a driver of breast cancer.

Following that paper, a study of Ukranian patients who developed thyroid cancer following the 1986 Chernobyl nuclear disaster found the mutation’s presence in a notable number of cases.

The mutation or its variants have now come to be associated with nearly two dozen different types of cancers.

“The estimate now is that these NTRK fusions are present in about one per cent of human tumors, so what started as a super-rare finding has turned into something with very broad applicability,” said Sorensen.

As the mutation his team discovered in 1998 began to appear more and more frequently, the pharmaceutical company Loxo Oncology took notice and began developing a drug that would target the enzyme associated with NTRK fusion cancers.

Larotrectinib, the end result of their joint endeavour with Bayer Pharmaceutical, works by binding with receptors on the mutant enzyme that inhibit cell growth, effectively attacking the cancer development at its source. Such a drug has the potential to be much more effective at treating cancers while having fewer adverse side effects because of the specific mechanism with which it operates.

Early clinical trials of the drug have yielded promising results, and larotrectinib was granted limited approval by the US Food and Drug Administration in late November of 2018. It is currently under review by Health Canada.

Sorensen said that he is often asked if he will profit financially from the development of the new drug, but he emphasized that the development of a commercially-viable product was never a goal of any of the team that originally discovered ETV6-NTRK3. “We’re scientists, we do it for the sake of discovery and finding new things,” he said.

He also expressed a feeling of immense satisfaction at having been part of a unique process of discovery that has led to tangible positive changes in the lives of cancer patients.

“It’s good for people in the lab now to see that what they do can have some meaning,” he said. “It’s not just a bunch of scientists playing in a sandbox … but it actually means something to patients.”