Why do some lung cancers stop responding to drugs that once worked? And why does the immune system sometimes fail to recognize and destroy tumors?
Pathologist Katerina Politi, PhD, has spent more than two decades pursuing those questions, and her team at Yale School of Medicine is now closer to finding answers that could reshape how patients are treated. “There are specific genetic alterations in tumors that encode proteins that lead to activation of signaling pathways that the cancer cells then rely on to survive and grow,” says Politi, the Joseph A. and Lucille K. Madri Professor of Pathology. “So can we use drugs to target those specific, altered proteins or other relevant molecules in the cancer cells? That’s one of the things that we’re interested in.”
The Politi Lab marked its 15-year anniversary last summer. During this time, many changes that cause lung cancer have been identified. Targeted therapies—drugs matched to those specific changes—have been developed. These medications work well for a while, but drug resistance develops and the therapy stops working.
“Another area of investigation in the laboratory is understanding mechanisms of drug resistance,” says Politi. “How do tumors that initially were sensitive to a specific drug become resistant and start growing again? This is one of the major challenges that limits the curative potential of targeted therapies.”
The lab also studies drug resistance with immunotherapies, in particular immune checkpoint inhibitors – or therapies that can engage the immune system to kill cancer cells. Lab members are studying why immune checkpoint inhibitors do not work in certain cases, and what happens when they work initially but then stop working. The lab studies tumors including new approaches to uncover genetic alterations to understand how tumors are “wired” by using model systems, cell lines, and preclinical models.
“We also use patient-derived models and we study patient specimens directly – which allows us to establish the clinical relevance of our findings,” she says.
How cancer cells evade the immune system
Through their work, Politi Lab members are making progress in their quest to understand some of the processes that drive resistance to immunotherapies in lung cancer.
Several years ago, a team at Yale found that when there is a loss of MHC I antigen presentation, cancer cells were not visible to T cells. MHC I antigen presentation on the surface of cells plays a crucial role in recognition by the immune system. The researchers determined that the loss of MHC I antigen presentation helped lung cancer cells evade the immune system and become resistant to immune checkpoint inhibitors.
“Now we are working on approaches to overcome resistance that is due to defects in MHC I antigen presentation,” Politi says. “That’s something that we are excited about.”
Politi’s interest in lung cancer dates to 2003 when she started as a postdoctoral associate in a lab at Memorial Sloan Kettering Cancer Center, studying how lung cell genetic alterations could make those tumors depend on those cells for their survival.
A culture of collaboration and discovery
In the 15 years since the lab was founded, Politi has trained scientists and researchers who share her passion for learning more about lung cancer. Working in her lab requires people who are excited about discovery and problem-solving.
“One of the important features of the scientists who come to the lab are people who can work together. We do a lot of work collaboratively within the lab and also outside of the lab, so that’s important. To advance the field, people have to work together.”
Mariana Do Carmo and Shannon Silva enjoy working in the lab.
“We always discuss the core questions of what we're trying to understand, and we try to identify the gaps in the current literature or what's really missing from the field,” Do Carmo says. “How can the models that we have in the techniques from our lab be used to address these questions and to really help us make progress in this area?”
“I regularly work with patient biopsies, so the work that we're doing is directly translatable to what's being seen in the clinic,” Silva adds. “I also like how we're able to take data that are coming out of clinical trials and use it to understand why certain results are being seen in the clinic.”
How basic research is saving lives
Politi looks forward to continuing her work and seeing new advances.
“If we look at the numbers, about 40,000 fewer people will die of lung cancer this year than 20 years ago, in part, because of advances in treatment approaches. Many of these advances can be linked to targeted therapies and immunotherapies,” she said.
“It’s incredible because, when I started, that was just the beginning of that era and it prompted the discovery of many targets in lung cancer that led to new therapies – and these have transformed the landscape for lung cancer treatment.” “It’s been amazing to watch how the field has changed and be part of it. When I give talks and speak to scientists and investigators, I say that it’s basic science foundations that made this progress possible. Without studies of cancer signaling, for example, we wouldn’t know how to target oncogenic drivers and without DNA sequencing, we wouldn’t know about cancer-associated mutations. Similarly, immune checkpoint inhibitors emerged from our understanding of T cell biology.”
“It’s amazing to see basic science discoveries having such a profound impact on the lives of people with lung cancer.”