Researchers in Nguyen Lab Seek Link Between Metastasis and Drug Resistance

Researchers in the Nguyen Lab at Yale School of Medicine focus on understanding how lung cancer metastasizes to distant organs, including the brain, and how cancer cells that reach the brain become resistant to drug therapy. The number of people who develop a brain metastasis from lung and other cancers can be 10-times greater than the number of patients with primary brain cancer.

“Metastasis is the major cause of mortality and brain metastases are particularly difficult to surgically remove or treat. And yet, we still have major gaps in our understanding of how this happens,” says Don Nguyen, PhD, associate professor of pathology and medicine (medical oncology and hematology) and principal investigator of the Nguyen Lab. “There are two sides to this problem. We focus, first, on identifying the changes in the cancer cells that allow them to adapt to their environment as they spread from one organ to another. Then we also study what happens to the cells that surround these cancer cells, which allows the tumors to evade our bodies’ natural defenses, such as our immune system.”

Patients that have metastatic disease also tend to be resistant to conventional therapies. Researchers in the Nguyen Lab concentrate on the idea that finding that intersection can improve patient outcomes. “From a clinical standpoint, we’re looking for what links the process of metastasis to drug resistance. We focus on lung cancer because we know that certain therapies can initially get into the brain,” Nguyen says. “But while some patients at first respond well to these therapies, many patients eventually progress with resistance. And when they fail to respond, they often develop brain metastasis. In fact, over the past 10 years, the incidence of brain metastasis has been rising across many cancer types.”

“We think that cancer cells prefer to spread as a group, and that there are particular molecules, both internal and external to cancer cells, which allow them to stay connected with one another and communicate with other cells in the brain. These abnormal connections ultimately protect these tumor cells as they spread to regions of the body that they are not supposed to,” Nguyen says.

While half the members of the Nguyen Lab study basic mechanisms and how cancer cells reach different organs, the other half study how once the cancer cells reach the brain, drug resistance is conferred to those cells. Lab members are also combining drugs in new ways to improve response to brain metastases. “In the lab, we’ve identified a number of targets where we think using combinations of existing or new drugs could be beneficial for patients,” Nguyen says.

The Nguyen Lab also collaborates with clinicians and investigators at Yale and around the world. “Our colleagues provide a rich source of technical expertise and knowledge. Our clinical collaborators always bring attention to new opportunities for translational research,” says Nguyen. For instance, the Nguyen Lab and their collaborators can safely, and with patient consent, collect tissue and fluid samples from patients undergoing surgery for a brain metastasis.

“We can get biopsies from the brain and from the liquid [surrounding it] at the same time. We are applying new molecular detection technologies to these samples to identify biomarkers in the blood and tissue with the hope that, eventually, we don’t have to rely on surgically removed brain tissue so much because that’s a very complicated, dangerous procedure,” he says. In addition to finding new biomarkers of disease progression, they hope to learn why some patients are more likely to develop brain metastases in the first place, and why certain cancer cells continue to spread into different regions of the central nervous system afterwards.

Lab member Savannah Kandigian, a PhD student in the Pathology and Molecular Medicine Program, studies different types of central nervous system metastases, looking at models of how tumor cells can enter brain tissue, the spinal fluid that surrounds the brain, or the protective barriers that surround the brain and spinal cord.

“I build model systems that allow us to recapitulate that and look at molecular mechanisms underlying those processes,” she says. “I also work with our clinical team to get samples from patients who are suffering from these different types of central nervous system metastases, and we can look at whether our model systems match what is actually going on in the patient when they have a metastasis in, say, the brain tissue or their spinal cord.”

Darin Dolezal, MD, PhD, instructor of pathology, brings his perspective as a practicing pathologist to the Nguyen Lab.

“I’m interested in improvements in diagnostic testing and I’m also interested in translational pathology and outcomes for patients,” Dolezal says. “We work on projects that are focused on circulating tumor cell biology, in particular circulating tumor cells that are found in the cerebral spinal fluid. We use the fluids to try to improve the ability to make patient diagnoses and also to improve predictive tests for patients’ responses to treatment.”

While it’s historically been thought that patients with brain metastases have poor prognoses, Dolezal says that with the advent of recent therapies, these patients are surviving much longer. “So there’s a mixture of how patients perform after, for example, surgery or radiation. We’re looking at trying to understand the reasons why some patients can survive for many years after having a brain metastasis and, unfortunately, why some patients can’t,” he says.

When it comes to recruiting new lab members, Nguyen says he looks for scientists who can bring new perspectives and are interested in the specific aspect of biology that applies to clinical disease. “The importance of preventing or treating metastatic disease is obvious. However, I’ve found that for trainees who are passionate about fundamental questions in biology and are committed to digging deeper into the underlying mechanisms, they are better served in the long run. If they don’t have that appreciation, they’ll be disappointed in how long it can take to answer these evolving clinical questions,” Nguyen says. “Not all of my trainees will see or treat patients. However, as a team we are inspired by our findings and their potential impact on patient care. At the heart of it, in order to stay motivated, it’s always about your drive to discover something new. “