For Ryan Englander, the goal is to connect scientific discoveries in the laboratory with better treatment options for real patients.
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BAR HARBOR AND CONNECTICUT—For some patients with lung cancer, immunotherapy can be a powerful treatment. Unfortunately, it doesn’t currently work for everyone.
That leaves doctors and scientists facing a difficult question: Why do some patients respond to these drugs while others don’t?
It also leads some scientists like Ryan Englander, an MD-PhD candidate at the University of Connecticut, on a quest to make things better for people with lung cancer.
Englander and other researchers at The Jackson Laboratory have uncovered a potential clue, one that lies not in the genes themselves, but in the way cancer cells process the genetic instructions used to make proteins.
The discovery, published recently in the journal Science, could eventually help doctors better predict which patients are likely to benefit from immunotherapy.
Englander’s findings represent something particularly meaningful: a connection between the intricate workings of cells and the lives of patients.
“That’s where I want to sit,” Englander said in an interview November 5, describing his interest in combining laboratory research with medicine. “Doing the nerd work and then bringing that into the real world to help real people.”
Helping people is the key for Englander as he continues his quest to combine research with practical applications for his future patients.
“They discovered previously overlooked changes that affect how cancer cells respond to signals from the immune system and are associated with differences in patient survival following immunotherapy,” Jackson Laboratory’s Patrick Skahill, a media relations manager, explained.
“Those findings,” Skahill said, “could eventually help doctors better predict which lung cancer patients are more or less likely to benefit from immunotherapy before treatment begins.”
What Englander found is a big deal a big step forward for his future and for future lung cancer patients.
Because of his research at the lab, Englander is the lead author in that article in Science, which was published on his birthday. He’s not even graduating until the end of this year, but he’s already making a difference in not just the world of science, but potentially in the world of people with lung cancer. There’s a lot of need for treatments.
“Lung cancer is the second most common cancer in the U.S. and the leading cause of cancer related deaths. While immunotherapy has transformed treatment for the disease, 60% to 80% of lung cancer patients do not respond to certain immunotherapies. For these patients, that can mean undergoing treatment without seeing the benefits they had hoped for, while doctors are left searching for answers,” Skahill explained.
With further research, Englander’s findings could help patients and their care teams make more informed treatment decisions.
“Obviously we need future clinical trials, but if it, if we can confirm it, then it would, it would actually help doctors match patients to therapy a lot better than we currently can,” Englander explained.
That, he said, would be amazing.
Looking beyond the genes
Englander’s research focused on a process called alternative splicing.
This, Skahill said, is more than traditional DNA testing. They focused on how lung cancer cells process genetic instructions.
“Your genes are kind of arranged on a string in DNA and alternative splicing is a process by which cells can kind of like mix and match pieces of your genes essentially that allows them to create different proteins, which are the things that go and do stuff in cells, different proteins from the same gene, which is really cool,” Englander explained.
Genes contain instructions that cells use to make proteins, the molecules responsible for carrying out many of the body’s essential functions. Before those instructions can be used, cells process RNA, removing certain sections and joining others together.
Alternative splicing allows cells to assemble those instructions in different ways, creating different versions of proteins from the same gene.
The process happens throughout the body and is essential to normal biological function. Researchers, though, are still learning how it can go wrong, particularly in cancer.
Newer technologies, including long-read RNA sequencing, have made it possible to examine these processes in much greater detail.
“We got access to some clinical trial data from a company called Genentech that we collaborated with, and they’ve been great to work with, very, very responsive and honestly awesome,” Englander said.
Englander and his colleagues used the technology to study lung adenocarcinoma, a common form of lung cancer. They examined tumor samples and compared the RNA patterns with those found in normal lung tissue.
The team identified an enormous number of RNA variations, including many that had not previously been catalogued.
Among those discoveries were two unusual versions of a protein called STAT2.
STAT2 plays an important role in the body’s immune response, helping cells receive and act on signals that can alert them to threats, including viruses and cancer.
The researchers found that lung cancer cells could alter how STAT2 is assembled, producing two distinct forms that interfere with immune signaling in different ways.
One form was essentially unable to perform its normal function. The other was more surprising, Englander said.
It could bind to an important immune-signaling partner, IRF9, and prevent that partner from participating in the normal signaling process.
In laboratory experiments, the altered protein actively suppressed interferon signaling, a pathway that helps coordinate the body’s immune defenses.
That means that cancer cells can find ways to interfere with the body’s ability to recognize and fight them.
A potential clue to immunotherapy response
The researchers then investigated whether the two altered STAT2 forms might be associated with how patients respond to immunotherapy.
Working with clinical trial data, the team examined patients who received atezolizumab, an immunotherapy drug, or docetaxel, a chemotherapy treatment.
They found that the relative levels of the two STAT2 RNA patterns were associated with patient survival.
Patients with a higher relative level of one pattern compared with the other had approximately twice the median overall survival of those in the lower-scoring group in the analyzed dataset.
The higher-scoring group also appeared to benefit more from atezolizumab compared with docetaxel, while the lower-scoring group did not show the same survival benefit in the analysis.
The findings suggest that the balance between these two altered STAT2 forms could eventually serve as a biomarker — a measurable biological feature that helps predict how a patient might respond to a particular treatment.
Currently, doctors have some biomarkers to help guide immunotherapy decisions, but they do not work perfectly.
“If we can confirm it, then it would actually help doctors match patients to therapy a lot better than we currently can,” Englander said.
The researchers also observed a similar association in a separate dataset involving metastatic urothelial cancer, suggesting the finding could have implications beyond lung cancer.
Englander emphasized that more research is needed before the discovery can be used in clinical practice.
The results are based on retrospective analyses of existing clinical data. Researchers will need to validate the biomarker in future prospective clinical trials before it can guide treatment decisions.
From the laboratory to the patient
Lung cancer was a particularly important focus for the research, Englander said, because of the disease’s significant impact on patients.
Lung cancer remains the leading cause of cancer-related death in the United States. The team also focused on lung adenocarcinoma, which is less strongly associated with smoking than some other forms of lung cancer and represents an increasingly significant proportion of cases.
“Lung cancer is one of the most common cancers, but it’s the leading cause of death by a pretty wide margin for both men and women,” Englander said.
The project began with a basic scientific question about how RNA splicing works in cancer cells, and over time, it developed into something with potential clinical applications.
“I don’t (know) if you saw the pancreatic cancer (data) that got described earlier and there was a standing ovation; that doesn’t happen at these meetings at all,” Englander said. “It’s all a bunch of very professional, hyper-professional scientists nicely clap, and they all stood up and lost their minds because we’ve never seen drugs like this in pancreatic cancer. It’s crazy. So that’s happening all the time. What we can do in the lab is 10 years ahead of what we can do in the clinic, maybe more. So the things that are coming down the pipeline are even better.”
He wants people to know that.
Knowing that gives people hope.
Englander collected the initial tumor samples in 2022. The project then evolved as the team identified and investigated the two STAT2 splicing events, eventually connecting their laboratory findings with patient outcomes.
For Englander, the research is an example of why he chose the MD-PhD path.
He completed his initial medical school coursework at the University of Connecticut before pursuing his doctoral research at The Jackson Laboratory. He has since returned to medical school and expects to graduate in the spring. He’s also already started his own company and received an NIH Fellowship.
He is currently applying to internal medicine residency programs with a research focus.
The paper is also a milestone in his scientific career: his first publication as lead author.
A rapidly changing field
While Englander talked about his discovery via Zoom, Thursday, he sat in front of a stack of books on a basement room.
Most of the books were by Tolkien whose tales feature hobbits—small, comfort-focused creatures mostly concerned with the joy and safety of home before heading off on seemingly impossible quests with wizards, elves, dwarves, and humans with remarkable powers fighting off impossible foes.
It’s hard to know if while on his own quest Englander is the wizard, wise and knowing in the magic of science, or the enthusiastic hobbit whose kindness and intent is to save Middle Earth, but either way his heart and ability to communicate his findings, his need and drive to be part of the group that makes a positive difference in the world resonates.
Englander pointed to advances in cancer treatment that are changing what doctors can offer patients, including new therapies for cancers that have historically been difficult to treat.
The progress, he said, is a reason to continue investing in research.
“We’ve spent so much money fighting the war on cancer, but we are winning,” Englander said. “And I think it’s important that we just keep that up.”
For now, the STAT2 discovery remains a promising research finding. It offers another piece of information about the complicated relationship between cancer and the immune system and provides another potential avenue for helping doctors determine which treatments may work best for individual patients.
For Englander, that connection between scientific discovery and patient care is the main point.
“Cancer sucks so bad,” he said. “It touches all of our lives….”
For him, there’s one goal of the research, the education, the funding, the discovery.
“We’re all doing it for patients,” he said.
The Bar Harbor Story is generously sponsored by Rick Osann Art.
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