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

Loredana Puca1,2, Katie Gavyert2, Verena Sailer2,3

  • 1Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.

Science Translational Medicine
|March 22, 2019
PubMed

Insights

Delta-like protein 3 (DLL3) is highly expressed in neuroendocrine prostate cancer, making it a promising target for treatment. Antibody-drug conjugate SC16LD6.5 shows efficacy in preclinical models and a patient with advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • Histologic transformation to small cell neuroendocrine prostate cancer is a resistance mechanism in advanced prostate cancer.
  • Delta-like protein 3 (DLL3) is a target for antibody-drug conjugates, initially developed for small cell lung cancer.

Purpose of the Study:

  • To investigate DLL3 expression in various prostate cancer subtypes and benign prostate tissue.
  • To evaluate the efficacy of the DLL3-targeting antibody-drug conjugate, rovalpituzumab tesirine (SC16LD6.5), in preclinical models and a patient with neuroendocrine prostate cancer.

Main Methods:

  • Immunohistochemical analysis of DLL3 expression in patient tumor samples (localized prostate cancer, castration-resistant prostate adenocarcinoma, castration-resistant neuroendocrine prostate cancer) and benign prostate tissue.
  • Assessment of DLL3 expression in circulating tumor cells.
  • In vivo efficacy studies using prostate cancer xenografts treated with SC16LD6.5.
  • Clinical case study of a patient with neuroendocrine prostate cancer treated with SC16LD6.5 on a phase 1 trial.

Main Results:

  • DLL3 is highly expressed in castration-resistant neuroendocrine prostate cancer (76.6%) and a subset of castration-resistant prostate adenocarcinomas (12.5%), with minimal expression in localized prostate cancer and benign prostate tissue.
  • DLL3 expression correlates with neuroendocrine markers, RB1 loss, and aggressive clinical features.
  • SC16LD6.5 demonstrated complete and durable responses in DLL3-expressing prostate cancer xenografts but not in DLL3-negative models.
  • A patient with neuroendocrine prostate cancer experienced a significant clinical and radiologic response to SC16LD6.5.

Conclusions:

  • DLL3 is preferentially expressed in castration-resistant neuroendocrine prostate cancer.
  • DLL3 is a viable therapeutic target for patients with DLL3-positive metastatic prostate cancer.
  • SC16LD6.5 shows potential as a treatment for patients with DLL3-expressing prostate cancer.

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