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Small cell lung cancer, or SCLC, is fraught with challenges. Patients are often diagnosed late so outcomes are poor; therapeutic advances have stalled due to lackluster funding and the disease, initially sensitive to chemotherapy, inevitably becomes resistant ― and fast.
While newly diagnosed patients receive biopsies, the tissue samples that are gleaned are usually too small to define the cancer’s molecular subtypes via immunophenotyping or deep genomic profiling, tests that tell oncologists what treatment might work best.
Clinicians and patients desperately need a reliable, noninvasive way to profile (and treat!) these tumors.
Now thanks to a new $1.5 million grant from the Andy Hill Cancer Research Endowment (CARE) Fund, Fred Hutch Cancer Center biologist David MacPherson, PhD, and computational biologist Gavin Ha, PhD, plan to bring just such a tool to the clinic.
“Recognizing the need to phenotype SCLC, we developed a new cell-free DNA sequencing assay, SCLCpheno-seq,” said MacPherson, who holds the Vinh Bui and Tram Le Endowed Chair for Lung Cancer and is a professor within the Human Biology and Public Health Sciences divisions. “This new first-of-its-kind assay will profile genomic and transcriptional features in plasma samples.”
MacPherson said the new assay will soon be used as a tool to “improve clinical responses and to detect transformation of non-small cell lung cancer to SCLC.” Funding from the grant will be used to validate the assay’s effectiveness in key clinical sample sets and link biological phenotypes to patient outcomes in a completed clinical trial.
“We hope it will accelerate the implementation of this innovative assay,” MacPherson said.
What we know about small cell lung cancer
Around 15% of lung cancers are classified as “small cell,” so named for the way the cancer cells appear under a microscope when compared to normal cells or the other major subtype, non-small cell lung cancer.
Small cell lung cancer, the kind most often linked to smoking, usually begins in the lung’s bronchi, the major airways in the middle of the chest that lead to the lungs. SCLCs are classified as neuroendocrine tumors, an aggressive subtype that grows rapidly.
Most SCLCs are initially treated with chemotherapy, however, the tumors quickly become resistant, and the disease continues to spread. As a result, the combined five-year survival rate for this disease (local, regional and metastatic) is around 9%.
MacPherson, who’s researched SCLC and its puzzlingly persistent resistance to chemotherapy for more than a decade, burrowed deep into the tumor’s genetics for answers. In 2025, he and his team identified KEAP1 loss as a key culprit behind SCLC’s storied chemoresistance (KEAP1 is a key regulatory protein), but further research revealed additional genes that might become promising targets for antibody drug conjugates or other potential therapies.
“Small cell lung cancer only rarely harbors activating mutations in oncogenic drivers with available targeted therapies, and gene mutations have not yet proven informative for selecting patients for biomarker-driven therapies,” MacPherson wrote in his grant proposal. “There is increasing appreciation that this cancer exhibits different molecular subtypes based not on DNA mutations but on activity and high expression of one of the master regulatory transcription factors ASCL1, NEUROD1 or POU2F3.”
A liquid biopsy assay that reveals expression and activity of these key clinically relevant genes, MacPherson wrote, could help direct the right therapies to the right patients ― precision oncology’s north star.
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When lung cancer switches gears
In addition to identifying potential targets, the new assay will also help clinicians ascertain whether patients with non-small cell lung cancer, or NSCLC, have acquired resistance that’s transformed their common subtype to the less common small cell subtype.
According to MacPherson, these “transformation events” often go undiagnosed.
“Repeat biopsies that provide pathologic evaluation are often not performed,” he said. “Moreover, a single biopsy may not be representative of the histological heterogeneity following SCLC-transformation between the metastatic sites.”
The new non-invasive assay ― a simple blood test ― could be used in the clinic “to identify transformation to SCLC and quantify phenotypic heterogeneity.” Grant funds will be used to validate the usefulness of the SCLCphenoseq2 assay in discerning these transformations, as well.
Looking ahead, MacPherson and his colleagues believe their new assay will help pioneer better strategies for stratifying lung cancer patients into future prospective clinical trials.
“We want to pave the way to improve clinical responses by determining biological phenotypes that cannot be achieved with current standard of care,” he said, adding that Fred Hutch has filed a patent application covering the methods utilized in the assay.
CARE from the state
The Andy Hill Cancer Research Endowment (CARE) Fund is a public-private partnership established by the Washington State Legislature in 2015. It invests in innovative cancer prevention, treatment and clinical trial diversity projects across the state, with matching funds provided by a non-state entity.
The SCLC project, “Implementing a novel liquid biopsy assay to phenotype small cell lung cancer for clinical application,” will be led by MacPherson and Ha, an associate professor within the Public Health Sciences Division and affiliate investigator in the Human Biology Division. De-identified patient samples will be provided by Keith Eaton, MD, PhD, a professor in Fred Hutch’s Clinical Research Division and the medical director of Quality & Value.
Other key collaborators include clinical and translational researchers Afshin Dowlati, MD, of Case Western Reserve University in Cleveland, and Charles Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, as well as Seattle area patient advocate Janet Freeman-Daily, who’s lived with metastatic lung cancer for several years. Read Janet’s story.
The grant was one of three awarded this cycle by the CARE Fund via its Implementation and Outcomes Research mechanism, which supports innovative and meritorious cancer researchers and teams seeking to translate promising research and scientific discoveries into effective interventions, tools, devices, technologies or therapeutics related to cancer.
