Detection of SEZ6, a Therapeutic Target, in Medullary Thyroid Carcinoma

Bin Xu, Marina K Baine, Achim Jungbluth, Anas Alabkaa, Rene Serrette, Dibisha Roy, Charles M Rudin, Alan L Ho, Eric Sherman, Snjezana Dogan, Ian Ganly, Natasha Rekhtman, Ronald Ghossein
The Journal of Clinical Endocrinology & Metabolism, Volume 110, Issue 7, July 2025, Pages 2041–2046
https://doi.org/10.1210/clinem/dgae672

Abstract

Context

Seizure-related 6 homolog (SEZ6) is a cDNA that is strongly associated with neuroendocrine differentiation. Recently, SEZ6 expression was found in a subset of small cell lung carcinoma (SCLC). Furthermore, ABBV-011, a novel antibody-drug conjugate targeting SEZ6 has been developed and is currently in a clinical trial for the treatment of SCLC and neuroendocrine neoplasms, including medullary thyroid carcinoma (MTC).

Objective

We herein present the first evidence that SEZ6 is highly expressed in MTC.

Methods

SEZ6 immuno-expression was studied in 78 MTCs and correlated with clinicopathologic characteristics, outcome, and molecular profile.

Results

SEZ6 was highly expressed in primary tumors, regional recurrence, and distant metastasis. Using 2 different SEZ6 antibody clones, SC17.14 and 14E5, SEZ6 immunopositivity was seen in 91% to 93% of primary MTCs, 100% of regional recurrence, and 75% to 83% of distant metastasis. High level of SEZ6 immuno-expression determined using H score was associated with male sex, advanced stage, and extrathyroidal thyroidal extension. There was no correlation between SEZ6 expression and outcome or RET/RAS mutation status in MTC. The frequency of SEZ6 positivity in MTC without RET/RAS mutations was 83%.

Conclusion

SEZ6 may serve as a novel biomarker for MTCs. Although SEZ6 lacks any prognostic values in MTC, its positivity in 91% to 93% of MTCs, including MTCs without RET and RAS mutations, renders SEZ6-targeted antibody-drug conjugate therapy a promising targeted therapy for MTCs.

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