Gale and Ira Drukier Institute for Children's Health

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

TitleDelta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer.
Publication TypeJournal Article
Year of Publication2019
AuthorsPuca 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 AJ, Sboner A, Wang Y, Dittamore R, Rickman D, Nanus DM, Tagawa ST, Elemento O, Mosquera JMiguel, Saunders L, Beltran H
JournalSci Transl Med
Volume11
Issue484
Date Published2019 Mar 20
ISSN1946-6242
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, 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.

DOI10.1126/scitranslmed.aav0891
Alternate JournalSci Transl Med
PubMed ID30894499
Grant ListP50 CA090381 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States