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. Tagawa; Olivier Elemento; Juan Miguel Mosquera; Laura Saunders; Himisha Beltran

doi:10.1126/scitranslmed.aav0891

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^*

^*Corresponding author for this work

Institute of Pathology

81 Citations (Scopus)

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 language	English
Article number	eaav0891
Journal	Science Translational Medicine
Volume	11
Issue number	484
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.aav0891
Publication status	Published - 2019

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)
Centers: University Cancer Center Schleswig-Holstein (UCCSH)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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), Article eaav0891. https://doi.org/10.1126/scitranslmed.aav0891

@article{4d81dffee5634902b311e86d1f348b76,

title = "Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer",

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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2019 The Authors, some rights reserved.",

year = "2019",

doi = "10.1126/scitranslmed.aav0891",

language = "English",

volume = "11",

journal = "Science Translational Medicine",

issn = "1946-6234",

number = "484",

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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, AJ, Sboner, A, Wang, Y, Dittamore, R, Rickman, D, Nanus, DM, Tagawa, ST, Elemento, O, Mosquera, JM, Saunders, L & Beltran, H 2019, 'Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer', Science Translational Medicine, vol. 11, no. 484, eaav0891. https://doi.org/10.1126/scitranslmed.aav0891

TY - JOUR

T1 - Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer

AU - Puca, Loredana

AU - Gavyert, Katie

AU - Sailer, Verena

AU - Conteduca, Vincenza

AU - Dardenne, Etienne

AU - Sigouros, Michael

AU - Isse, Kumiko

AU - Kearney, Megan

AU - Vosoughi, Aram

AU - Fernandez, Luisa

AU - Pan, Heng

AU - Motanagh, Samaneh

AU - Hess, Judy

AU - Donoghue, Adam J.

AU - Sboner, Andrea

AU - Wang, Yuzhuo

AU - Dittamore, Ryan

AU - Rickman, David

AU - Nanus, David M.

AU - Tagawa, Scott T.

AU - Elemento, Olivier

AU - Mosquera, Juan Miguel

AU - Saunders, Laura

AU - Beltran, Himisha

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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U2 - 10.1126/scitranslmed.aav0891

DO - 10.1126/scitranslmed.aav0891

M3 - Journal articles

C2 - 30894499

AN - SCOPUS:85063524578

SN - 1946-6234

VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 484

M1 - eaav0891

ER -

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

Abstract

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