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Sci Transl Med. 2019 Mar 20;11(484). pii: eaav0891. doi: 10.1126/scitranslmed.aav0891.

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

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Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, FC, Italy.
AbbVie Stemcentrx LLC, South San Francisco, CA 94080, USA.
Epic Sciences, San Diego, CA 92121, USA.
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.


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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