Project title: Biopsy specimen molecular stratification of metastatic pulmonary carcinoid

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Description

Dr. Derks will use state-of-the-art information on molecular subtypes in pulmonary carcinoid and work to translate this knowledge toward daily clinical practice in patients suffering with disseminated disease that has spread.

What critical NET problem/question will researchers try to answer?

Dr. Derks and his research team will explore whether it is possible to apply identified molecular subtypes in patients with disseminated pulmonary carcinoid disease. They will also investigate how common these subtypes are and whether they can be used to predict responses to different treatments and disease outcomes.

Why is this important?

Establishing a diagnosis in pulmonary carcinoid tumors based on a biopsy specimen is challenging and may affect the choice of treatment. Improving diagnostic capabilities on small tumor samples, combined with new molecular insights, may aid a clinician in providing the best treatment and improving the outcome for a patient.

What will the researchers do?

Dr. Derks will apply a combination of biomarkers to identify molecularly classified pulmonary carcinoid subtypes in patients who have disseminated disease. These biomarkers are applicable to small tumor samples. The research team will then evaluate patients’ treatments and outcomes for each identified subtype. Finally, they will establish an exploratory prediction model.

How might this improve treatment of NETs?

If the results of the study illuminate the further potential of the combination of biomarkers, this approach may help to pave the way toward tailored therapy in patients who have disseminated pulmonary carcinoid disease.

What is the next step?

In this study Dr. Derks and his team will provide insight into the different molecular subtypes in disseminated disease. Potential treatment response signals may be used to develop prospective studies that investigate biomarker-based drug treatment combinations.

Outcomes:

Thanks to your generous support, we have made important progress in understanding metastatic lung carcinoid. Our research focuses on identifying biological markers in tumor tissue that help us better classify these cancers and that may correlate with (new) treatment options.

Our first major study was published in the Journal of Thoracic Oncology and provides a strong scientific foundation for this work. In that study, we identified a panel of three markers—OTP, ASCL1, and HNF1a—that can divide lung carcinoid tumors into distinct biological subgroups. These markers were studied in tumor samples at the protein level. Building on this, we completed an additional validation study using 90 tumors from the lungNENomics cohort, where we compared both protein and genetic (RNA) information. This confirmed the reliability of our marker panel. The results are ready for publication and are currently under review.

Within our metastatic lung carcinoid project, we have established a unique worldwide cohort of more than 250 patients, with detailed tissue analyses available for nearly 200 tumors. This represents one of the largest and most comprehensively studied groups of patients with this rare cancer. The analysis of treatment outcome including somatostatin analogues, everolimus and capecitabine-temozolomide chemotherapy is still ongoing and will be published in the future.

Our findings thus far consistently show that the markers ASCL1 and HNF1a define biologically distinct tumor subtypes. These subtypes are not only biologically different—they also have important treatment implications. Tumors with HNF1a expression show strong expression of SSTR2a, a well-known therapeutic target used in current treatments. In contrast, tumors with ASCL1 expression frequently show expression of DLL3, a newer and promising therapeutic target. Importantly, in patients with metastatic disease, we observed ASCL1 expression in more than half of cases. This suggests that a substantial number of patients may benefit from treatments targeting DLL3.

These findings significantly advance the field by moving beyond traditional tumor classification based only on appearance under the microscope. Instead, we are defining lung carcinoid tumors based on their underlying biology, which is essential for precision medicine. Our work provides a clear scientific rationale for testing new DLL3-directed drugs specifically in patients whose tumors express this marker. Although securing funding for a large international clinical trial has been challenging, we continue to pursue this goal. In parallel, through collaboration we are preparing an investigator-initiated clinical study focused on DLL3 in lung carcinoid tumors.

Ultimately, this research brings us closer to more personalized treatment strategies. By identifying which tumors carry specific therapeutic targets, we aim to match patients to the treatments most likely to benefit them, improving outcomes and expanding options for those living with metastatic lung carcinoid.

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