Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer

Loredana Puca, Katie Gavyert, Verena Sailer, Vincenza Conteduca, Etienne Dardenne, Michael Sigouros, Kumiko Isse, Megan Kearney, Aram Vosoughi, Luisa Fernandez, Heng Pan, Samaneh Motanagh, Judy Hess, Adam J. Donoghue, Andrea Sboner, Yuzhuo Wang, Ryan Dittamore, David Rickman, David M. Nanus, Scott T. TagawaOlivier Elemento, Juan Miguel Mosquera, Laura Saunders, Himisha Beltran

Research output: Contribution to journalArticle

Abstract

Histologic transformation to small cell neuroendocrine prostate cancer occurs in a subset of patients with advanced prostate cancer as a mechanism of treatment resistance. Rovalpituzumab tesirine (SC16LD6.5) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) and was initially developed for small cell lung cancer. We found that DLL3 is expressed in most of the castration-resistant neuroendocrine prostate cancer (CRPC-NE) (36 of 47, 76.6%) and in a subset of castration-resistant prostate adenocarcinomas (7 of 56, 12.5%). It shows minimal to no expression in localized prostate cancer (1 of 194) and benign prostate (0 of 103). DLL3 expression correlates with neuroendocrine marker expression, RB1 loss, and aggressive clinical features. DLL3 in circulating tumor cells was concordant with matched metastatic biopsy (87%). Treatment of DLL3-expressing prostate cancer xenografts with a single dose of SC16LD6.5 resulted in complete and durable responses, whereas DLL3-negative models were insensitive. We highlight a patient with neuroendocrine prostate cancer with a meaningful clinical and radiologic response to SC16LD6.5 when treated on a phase 1 trial. Overall, our findings indicate that DLL3 is preferentially expressed in CRPC-NE and provide rationale for targeting DLL3 in patients with DLL3-positive metastatic prostate cancer.

Original languageEnglish
Article numbereaav0891
JournalScience Translational Medicine
Volume11
Issue number484
DOIs
Publication statusPublished - Jan 1 2019

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Puca, L., Gavyert, K., Sailer, V., Conteduca, V., Dardenne, E., Sigouros, M., Isse, K., Kearney, M., Vosoughi, A., Fernandez, L., Pan, H., Motanagh, S., Hess, J., Donoghue, A. J., Sboner, A., Wang, Y., Dittamore, R., Rickman, D., Nanus, D. M., ... Beltran, H. (2019). Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Science Translational Medicine, 11(484), [eaav0891]. https://doi.org/10.1126/scitranslmed.aav0891