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

被引：149

作者：

Puca, Loredana ^{[1
,2
,3
]}

Gavyert, Katie ^{[2
,3
]}

Sailer, Verena ^{[2
,3
,5
]}

Conteduca, Vincenza ^{[1
,4
]}

Dardenne, Etienne ^{[5
]}

Sigouros, Michael ^{[1
]}

Isse, Kumiko ^{[6
]}

Kearney, Megan ^{[7
]}

Vosoughi, Aram ^{[2
,3
,5
]}

Fernandez, Luisa ^{[7
]}

Pan, Heng ^{[2
,3
]}

Motanagh, Samaneh ^{[2
,3
,5
]}

Hess, Judy ^{[1
]}

Donoghue, Adam J. ^{[1
]}

Sboner, Andrea ^{[2
,3
,5
,8
]}

Wang, Yuzhuo ^{[9
]}

Dittamore, Ryan ^{[7
]}

Rickman, David ^{[5
]}

Nanus, David M. ^{[1
,2
,3
]}

Tagawa, Scott T. ^{[1
,2
,3
]}

Elemento, Olivier ^{[2
,3
,8
]}

Mosquera, Juan Miguel ^{[2
,3
,5
]}

Saunders, Laura ^{[6
]}

Beltran, Himisha ^{[1
,2
,3
,10
]}

机构：

[1] Weill Cornell Med, Div Med Oncol, New York, NY 10065 USA

[2] Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York, NY 10021 USA

[3] NewYork Presbyterian, New York, NY 10021 USA

[4] Ist Sci Romagnolo Studio & Cura Tumori IRST IRCCS, I-47014 Meldola, FC, Italy

[5] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10065 USA

[6] AbbVie Stemcentrx LLC, San Francisco, CA 94080 USA

[7] Epic Sci, San Diego, CA 92121 USA

[8] Weill Cornell Med, Inst Computat Biomed, New York, NY 10065 USA

[9] Univ British Columbia, Vancouver, BC V6T 1Z4, Canada

[10] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2019年 / 11卷 / 484期

关键词：

CIRCULATING TUMOR-CELLS; LINEAGE PLASTICITY; NOTCH; RECEPTOR; GENE; METASTASIS; ASCL1; HETEROGENEITY; SEGMENTATION; INHIBITION;

D O I：

10.1126/scitranslmed.aav0891

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：12

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