More than 150 lung cancer researchers, clinicians and patient advocates from around the country gathered at Fred Hutch Cancer Center in Seattle last week for a two-day working meeting of the Fred Hutch Lung Specialized Project of Research Excellence, or SPORE, sharing insights on immunotherapies, the search for new molecular targets, multi-cancer detection tests and the harsh realities of life with a lung cancer diagnosis.
Kicked off by McGarry Houghton, MD, principal investigator for the Fred Hutch Lung SPORE, the meeting brought together investigators from Dana-Farber, Yale, Emory, UT-Southwestern, MD Anderson and other leading cancer centers around the country, all of whom collaborate with the Lung SPORE to fast-track new breakthroughs to those being treated (or at risk) for lung cancer. Houghton holds the Satya and Rao Remala Family Endowed Chair.
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Despite improvements in therapy, the lung cancer field as a whole remains drastically underfunded and under-researched. Lung cancer deaths in the U.S. outnumber those of breast, prostate and colorectal cancer combined, but lung cancer research historically receives a fraction of the money other cancers receive, in part due to the stigma surrounding its link to smoking. Read more about the ‘lung cancer blame game.’
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Learn more about our targeted approach to the diagnosis and treatment of lung cancer.
Statistics, however, show that up to 20% of lung cancer diagnoses occur in those who’ve never smoked. In addition to tobacco products and second-hand smoke, the disease can be driven by exposure to radon, asbestos, air pollution or other toxins; inherited mutations also play a role.
“We’re here to hit upon the areas of lung cancer where we all need to do better: targeted therapies, immune-based therapies, small cell lung cancer, early detection and screening and basic lung cancer biology and foundational understanding,” Houghton said in his opening remarks.
Toward that end, Houghton and Fred Hutch Lung SPORE Strategy Director Jessica Paulishen packed each session with recognized leaders, folded in patient advocate perspectives with each topic, featured a pair of lunchtime poster sessions and included two internationally recognized keynotes: immunotherapy expert Philip Greenberg, MD, of Fred Hutch and lung cancer research leader Charles Rudin, MD, PhD, of Memorial Sloan Kettering. (Greenberg holds the Rona Jaffe Foundation Endowed Chair.)
― Fred Hutch clinical researcher and oncologist Dr. Kevin Levine
Funded by the National Cancer Institute, there are currently 56 Specialized Projects of Research Excellence, or SPOREs, in the U.S., all of which promote collaborative multidisciplinary translational cancer research.
Fred Hutch’s five-year Lung SPORE grant was originally awarded in 2019. Last fall, the Lung SPORE was renewed for another five years with a $12.3 million grant.
Designed to encourage innovative research that can be adeptly translated into new patient therapies, the Fred Hutch Lung SPORE currently has three main focus areas, each representing critical barriers to improving lung cancer survival rates.
Houghton and Fred Hutch lung cancer oncologist Christina Baik, MD, MPH, co-lead a project designed to target neutrophils to enhance the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer. Currently, ICIs are only effective in about 20% of patients. In pre-clinical studies, however, Houghton and Baik found that inhibiting or depleting neutrophils enables ICIs to clear tumors better. The team will soon launch a clinical trial pairing a checkpoint inhibitor with a drug that reduces levels of tumor-associated neutrophils, aiming to help the 30% of NSCLC patients whose cancers have an overabundance of these immune “first responders” that cancer commonly hijacks to evade detection.
Another project, led by Greenberg and medical oncologist and immunotherapy expert Sylvia Lee, MD, aims to engineer T cells to target the KRAS mutations behind many metastatic lung cancers by creating a coordinated CD4 and CD8 T cell response that can sustain anti-tumor activity. If effective, this approach could result in long-lasting immune responses in patients. The team is testing this approach in an ongoing clinical trial.
Small cell lung cancer (SCLC), which has few effective treatment options, is the focus of a third project, led by Fred Hutch scientist David MacPherson, PhD, holder of the Vinh Bui and Tram Le Endowed Chair for Lung Cancer and medical oncologist Keith Eaton, MD, PhD, clinical director of Thoracic Oncology and Head & Neck Oncology. This team is focusing on increasing the ability of the immune system to recognize these cancers, as they largely go undetected. Their goal is to study a novel therapeutic target, LSD1 demethylase inhibition, to see how it might work to improve responses to immunotherapy in SCLC patients, as well as identify molecular signals to help identify patients who’ll respond best.
The SPORE meeting was organized by Houghton, MacPherson, Baik and translational biologist Alice Berger, PhD.
Cancer genomics expert Matthew Meyerson, MD, PhD, of Dana-Farber, one of the discoverers of EGFR, the most common actionable mutation in NSCLC, opened the meeting with a discussion of new compounds and combinations to tackle drug resistance in EGFR and HER2 mutant lung cancers, an ongoing issue in this cancer.
“We and others, including your president here, Dr. Tom Lynch, discovered EGFR mutations in lung adenocarcinoma that are not only driving the disease but were associated with response to already-found EGFR inhibitors,” Meyerson said.
But not all patients are able to benefit from these treatments, due to genetic and other factors.
Much of the two-day workshop was dedicated to identifying the disparities that still exist in lung cancer research, early detection and therapies, with a number of speakers drilling down into the transcriptional factors driving drug tolerance (and drug resistance) as well as their efforts to identify rare drivers and driver alterations in the disease.
KRAS and EGFR mutations make up about a third of all driver alterations in lung cancer, said clinical researcher and medical oncologist Kevin Levine, MD, PhD, a member of the Berger Lab. Others are driven by ALK fusions or a handful of identified rare driver alterations.
But about a quarter of lung cancers are driven by what’s known as “driver-negative” disease.
“The driver behind my work is trying to identify novel rare alterations in NSCLC both by classifying variants of unknown significance as whether or not they are a driver and also to identify novel events that are missed by other technologies,” he said, sharing data on a previously unknown HER3-BCAR4 mutation he found to be highly expressed in a handful of NSCLC patients.
“If we can identify the drivers of these ‘driver-negative’ non-small cell lung cancers, patients will benefit,” he said. “Identifying them will drastically change patient outcomes.”
Former rocket scientist and longtime lung cancer patient advocate Janet Freeman-Daily spoke on the importance of patient research advocates, or PRAs.
“Let us help you help us,” she said during her virtual talk, reminding attendees that research advocates bring lived experience, deep connections to the patient community and crucial patient buy-in to the research arena.
Sydney Barned, MD, who was diagnosed with lung cancer during her residency and progressed to metastatic disease in 2022, spoke of the challenges of living with stage 4 lung cancer while trying to work and thrive.
“I would love you to look into survivorship care and the side effects of all of these medications,” she said. “I live with chronic fatigue which drives me mad and interferes with my work. It doesn’t help if you sleep more. It doesn’t really help to exercise. I’ve had to learn to live with it. We need more research on the downstream effects of the molecules you folks are researching.”
What can we do better for survivors?
“If we’re going to be living longer, we have to think outside of just the tumor response,” Barned stressed. “We have to think how patients are going to live on a medication. We want to create long-term survivors, but if I’m having a miserable time on a drug, how adherent am I going to be? Looking at how side effects could be mitigated is important. Survivorship science is important.”
Barned also encouraged researchers to work with advocates on the design and implementation of studies and clinical trials, encouraging researchers to engage with advocates at the very beginning of the research process, rather than at the end.
“Patients will help you think outside of your box,” she said. “Different perspectives are beneficial.”
Learn more about lung cancer risk and prevention
Greenberg provided an overview of various kinds of immunotherapy and his efforts to “take T cells where natural evolution hasn’t ― toward sustained function in the tumor microenvironment.”
Fred Hutch’s Mikel Ruterbusch, PhD, spoke on ways to improve CD4+ and TCR T-cell therapy for solid tumors through IL1sR, or Interleukin-1 Receptor signaling, a biological pathway that drives the body’s acute inflammatory and immune responses. Fred Hutch’s Kristin Lastwika, PhD, and Paul Lampe, PhD, gave perspectives on lung cancer screening and early detection, including work being done by the Fred Hutch-based Cancer Screening Research Network, which is researching the efficacy of multicancer early detection tests, or MCDs.
Fred Hutch pulmonologist and medical director of the Lung Screening Program Matthew Triplette, MD, MPH, also spoke on the disparities that still exist in screening.
“Lung cancer screening is effective as practiced with a low dose CT, but it’s not as effective as it could be,” he said. “There could be a potential role for biomarkers in lung cancer early detection. More than 50% of all lung cancers are missed by screening guidelines. And ‘pack-years’ based guidance is inherently inequitable.”
Many in the audience agreed, including one member who pointed out that lung cancer screening guidelines are the only guidelines that are based on both age and behavior.
“Why can’t we push to eliminate the behavior aspect of the screening eligibility?” she asked, noting the number of nonsmokers with the disease. “Can we just keep it age-based as we do with other cancers?”
By next year’s meeting, perhaps we’ll have an answer.
Diane Mapes is a senior editor and writer at Fred Hutch Cancer Center, who's written for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor and patient advocate, you can reach her at dmapes@fredhutch.org or doublewhammied.com / @double_whammied / @doublewhammied.bsky.social. Just diagnosed and need information and resources? Visit our Patient Care page.
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