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Cancer Res. 2017 Jul 15;77(14):3931-3941. doi: 10.1158/0008-5472.CAN-17-0299. Epub 2017 May 9.

Noninvasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer.

Author information

1
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College and The Rockefeller University, New York.
4
Stemcentrx, Inc., South San Francisco, California.
5
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Weill Cornell Medical College, New York, New York.
8
Department of Chemistry, Hunter College and the Graduate Center of the City University of New York, New York, New York.
9
Ph.D. Program in Chemistry, the Graduate Center of the City University of New York, New York, New York.
10
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York. lewisj2@mskcc.org poirierj@mskcc.org.
11
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. lewisj2@mskcc.org poirierj@mskcc.org.

Abstract

The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, although orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed 89Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a noninvasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with 89Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient-derived xenograft models. Cancer Res; 77(14); 3931-41. ©2017 AACR.

PMID:
28487384
PMCID:
PMC5534176
DOI:
10.1158/0008-5472.CAN-17-0299
[Indexed for MEDLINE]
Free PMC Article

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