The path to discovery rarely follows a straight line.
In 2015, as a post-doc researcher at Pfizer, Michael Arensman got an early lesson in this maxim. At the time, he set out to study the protein xCT, a transporter that carries nutrients into cells, and its role in T-cell proliferation. As a young scientist, he was eager to have his results published and contribute to the field of immunology.
But about a year into the study, his hypothesis failed. He took his unexpected results, however, and pivoted his research to make novel discoveries about xCT’s role in tumor survival, which ultimately could lead to a new cancer therapy. Now a senior scientist at Pfizer, Arensman’s xCT study was recently published in the Proceedings of the National Academy of Sciences.
For Arensman, it illustrates the circuitous nature of scientific research. “When you read a scientific paper, the authors usually describe a straightforward path as to how the project materialized,” says Arensman, who is based at Pfizer’s Pearl River, N.Y. research site. “But in reality, our stories have so many twists and turns.”
Arensman’s initial hypothesis was built upon existing research done in vitro, in petri dishes, showing that xCT’s transport of the amino acid cystine was crucial for cell survival. Scientists had hoped that the amino acid carrier could be used as a potential drug target to stop T-cell proliferation in autoimmune disorders. But when he replicated this study in vivo, in mouse models, he got unexpected results: the cells from the knockout mice — meaning their xCT had been genetically deleted — were able to proliferate at the same rate as the cells from normal mice.
For scientists, getting this “negative data,” meaning there’s no difference between the experimental arm and control arm, can be disappointing because it leaves them with limited chances of getting published. “I was frustrated because I expected there to be a difference,” says Arensman. “I kept doing it over and again.”
"When you read a scientific paper, the authors usually describe a straightforward path as to how the project materialized. But in reality, our stories have so many twists and turns."
What Arensman eventually concluded is that results from a petri dish don’t always translate into real life models, such as a mouse or human. He reasoned that T-cells can proliferate without xCT by using substitute transporters to acquire essential nutrients. But in these cases, says Arensman, publishing “negative data” serves a purpose. “It saves scientists from going on a wild goose chase for a drug that won’t help anybody.”
Arensman then took his “negative data” — that xCT is not crucial for the immune system — and wondered if that knowledge could be useful in fighting cancer. “In developing cancer treatments, we want to inhibit the tumor growth, but we don’t want to adversely affect the immune response, because that’s fighting the cancer as well,” says Arensman.
Prior research had already shown that xCT played a role in tumor survival because it helps form antioxidants in cells. While we generally think of antioxidants as a good thing, cancer cells also use antioxidants to fight oxidative stress and promote their proliferation. By blocking xCT, scientists found that tumor growth could be slowed.
Arensman then combined these two concepts to study cancer in mice.
Tumor-bearing mice given immunotherapy, a type of treatment that activates T-cells to kill tumors, only had a 30% survival rate. Remarkably, when xCT was deleted in the tumors and the mice were given immunotherapy, they had a more than 95% survival rate. “We showed that by itself xCT knockout can delay the tumor growth, but when you combine it with something that stimulates the immune system, it can totally kill the tumor,” he says.
While these early findings are limited to mice, it opens up a new path of inquiry to study xCT in combination with immunotherapy. It also helped Arensman realize that science can truly lead to unexpected places. “All of these disciplines can intersect,” he says. “We started out studying immunology and ended up applying our findings to cancer research.”