Episode #46 Stopping Lung Cancer Before It Starts with Drs. Steven Dubinett & Avrum Spira

Albert Rizzo:
Welcome to Lungcast, the monthly respiratory health podcast series from the American Lung Association and medical news site HCP Live. I’m your host, Dr. Albert Rizzo, Chief Medical Officer of the American Lung Association.

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Today’s discussion will be on the topic of intercepting lung cancer. Right now about 90% of the emphasis is on treatment of cancer, but the belief is that ultimately the emphasis will shift to prevention, as well as treatment of those cases that sneak through. There’s a perception that cancer risk reduction is passive—such as not smoking or avoiding inhaled carcinogens—but cancer interception is an active way of combating cancer at earlier and earlier stages.

The biology behind interception is increasingly solid. In fact, this was published in 2011 by Dr. Elizabeth Blackburn, Nobel Prize winner in 2009. She was part of the early review team of the research we’ll be talking about today.

We’re speaking with the principal investigators of our Lung Cancer Interception Team. This multi-year research project was initially funded by the American Lung Association, Stand Up to Cancer, and LUNGevity. Based on the initial findings, the project has been extended another three years with continued support.

Today we have Dr. Steven Dubinett, Dean of the David Geffen School of Medicine at UCLA, Associate Vice Chancellor for Research, Distinguished Professor in the Departments of Medicine, Pathology, and Pharmacology, and founding director of the UCLA Clinical and Translational Science Institute. He has built a translational research program applying discoveries in inflammation, immunity, and lung cancer to the clinical environment.

We also have Dr. Avrum Spira, Professor of Medicine, Bioinformatics, and Pathology at Boston University. He built a translational research program focused on genomic alterations in lung disease, leading to a molecular test for early detection of lung cancer. He is also the Global Head of Interventional Oncology at Johnson & Johnson, leading R&D efforts to deliver therapies directly into lung tumors.

Thank you both for being here and welcome.

Avrum Spira:
Thank you, Al. Great to be back. We’re very excited to update you on the progress we’ve made, and more importantly, to share the next wave of research that the American Lung Association and LUNGevity are funding. We believe this work will bring our discoveries closer to the clinic to intercept lung cancer and those at risk.

Albert Rizzo:
Thank you. Just a few background notes: lung cancer remains the leading cause of cancer death in the U.S. and worldwide, despite low-dose CT screening efforts. Uptake of screening remains low, despite its proven effectiveness and advocacy efforts. Even with great strides in targeted therapy and immunotherapy, the challenge is that we cannot detect cancer early enough—or ideally, intercept it before it becomes cancerous.

We last spoke with you both in November 2020, almost four years ago, on Episode 4 of Lungcast. Could you summarize the results of the first phase of your research, which involved establishing a precancer genome atlas and identifying markers to help distinguish benign versus malignant nodules, as well as markers to help in precision interception of cells in clinical trials?

Avrum Spira:
Thank you, Al. I’ll start with what we’ve done over the past four years, focusing on the precancer atlas for squamous cell lung cancer, and then I’ll hand it to Steve to cover adenocarcinoma.

The idea was to create a molecular atlas—a map of all the cellular and molecular changes as a premalignant lesion progresses toward lung cancer or regresses away. With that map, we can develop biomarkers to predict which lesions are destined to become invasive cancer, and also identify novel biological targets for intervention.

One of the biggest accomplishments has been building a coalition across medical centers in the U.S. and Europe, collecting samples from over 400 patients with premalignant lesions—the largest cohort in the world. That was a huge logistical challenge, but by collaborating, we now have the foundation to move forward.

In squamous lesions, studied longitudinally through bronchoscopy, we found that the immune microenvironment is a key determinant of progression. Specifically, lesions with an immunosuppressive environment were more likely to progress to invasive cancer. With tools like single-cell sequencing, we’ve identified the immune cell types that are lacking and the epithelial changes driving that immunosuppression. These insights give us both biomarkers and novel therapeutic targets.

Steve, let me hand it over to you for adenocarcinoma.

Steven Dubinett:
Thanks, Avrum, and thank you, Dr. Rizzo, for the American Lung Association’s support.

On the adenocarcinoma side, we studied early molecular, cellular, and immunologic changes. Using surgical resections, subsolid and solid nodules, and normal lung tissue, we performed single-cell RNA sequencing and other validation techniques.

We found, much like in squamous cell carcinoma, a suppression of immune surveillance during the earliest stages of adenocarcinoma. Natural killer cells and effector T-cells decline, while regulatory T-cells increase. The tumor environment, including fibroblasts and type II alveolar cells, appears to deregulate the extracellular matrix and limit immune infiltration.

This forms the beginning of an atlas of early adenocarcinoma. Going forward, we’ll expand to include spatial and epigenetic profiling to better understand regulation and cell-cell interactions.

Avrum Spira:
In addition, we’ve worked on distinguishing benign from malignant pulmonary nodules. Over a million nodules are found annually in the U.S., most benign. We’ve developed a nasal epithelial gene expression signature that predicts whether a deep-lung nodule is malignant. This, combined with imaging-based radiomics and a blood-based test looking at DNA fragmentomics, forms a multimodal approach.

Finally, in early-stage patients receiving neoadjuvant therapy, we’ve partnered with Hopkins and others to develop predictive biomarkers of response and recurrence risk, including circulating tumor DNA assays.

Albert Rizzo:
Thank you. Having followed your work from the beginning, it’s clear how things are falling into place. A couple of questions: you’ve explained your future research aims, including robotic bronchoscopy for longitudinal sampling and spatial/epigenetic profiling. What is the timeline for moving into patient trials?

Avrum Spira:
We’re still a few years away. First we need to identify targetable events, test them in preclinical models, and then move into first-in-human trials. But robotic bronchoscopy provides a proof of concept, not just for sampling, but potentially for directly delivering therapies into premalignant lesions.

Steven Dubinett:
I agree. At the same time, we’re advancing risk prediction algorithms, working with engineers at UCLA and MIT. Using a single CT scan, these tools can predict risk of developing lung cancer within one year, and out to six years, regardless of the CT appearance. Combining that with nasal and blood biomarkers will allow us to treat risk more precisely.

Albert Rizzo:
That brings me to the lung environment. We once thought of the lung as sterile, but now we know there’s a microbiome. Do your findings suggest links between the microbiome, inflammation, and tumorigenesis?

Steven Dubinett:
Yes. Dysbiosis—imbalances in the microbiome—can lead to inflammatory cytokines like IL-17 and IL-1β, which disrupt epithelial regulation and promote malignant transformation. We see parallels between these pathways and those driving cancer in our studies.

Avrum Spira:
While we’re not directly studying the microbiome in this phase, we are biobanking samples from our cohorts so they can be analyzed in the future with advanced sequencing. That’s a valuable asset created by this project.

Albert Rizzo:
One final question: you mentioned fragmentomics in blood-based biomarkers. How does that compare with other approaches like proteomics or mutation-based ctDNA assays?

Avrum Spira:
Fragmentomics is unique. Instead of looking for rare mutations, it examines the size patterns of DNA fragments shed by tumor cells, which differ biologically from normal cells. It’s proven to be sensitive and specific across several cancer types, and we’re excited about its promise in lung cancer.

Albert Rizzo:
Well, I want to thank you both for your time today and for this exciting work on intercepting lung cancer.

For listeners who want to hear more, we have an archive of discussions including Episode 16 on lung cancer CT screening with Dr. James Mulshine, Episode 34 with medical oncologist Dr. Carolyn Presley, and Episode 41 with thoracic surgeon Dr. John Spicer on evolving lung cancer treatment.

Be sure to subscribe and rate Lungcast on your preferred platform, and visit lung.org and hcplive.com for more news and resources.

And remember, aside from these educational endeavors, the American Lung Association through its Research Institute funds investigators in all aspects of lung disease. You can learn more at lung.org/research.

Until next time, I’m Dr. Albert Rizzo, reminding you that if you can’t breathe, nothing else matters.