ProsTIC/PCF Global Webinar 2023: DLL3: A New Target for Radioligand Therapy in Neuroendocrine Differentiated Prostate Cancer

The Prostate Cancer Foundation (PCF) hosted the 2023 ProsTIC PCF Global Webinar providing a contemporary overview of novel prostate-specific membrane antigen (PSMA)-targeted alpha emitting agents and new targets for prostate cancer.

This session included a presentation by Dr. Michael Morris and Dr. Lisa Bodei discussing DLL3, a new target for radioligand therapy in neuroendocrine differentiated prostate cancer. Dr. Morris started this presentation by noting that lineage plasticity includes loss of tumor suppressors, activation of oncogenic drivers, and epigenetic changes:treatment resistance flow
Dr. Morris notes that DLL3 expression is upregulated in treatment-emergent neuroendocrine differentiated prostate cancer and is associated with a poor prognosis:image-1.jpg
Currently, targeted approaches to DLL include immunotherapy and unselected antibody drug conjugates. AMG 757 is a half-life extended bispecific T-cell Engager (BiTE) targeting DLL3 in small cell lung cancer (NCT03319940), with the BiTE molecules engaging a patient’s own T cells to attack and eradicate cancer cells:t cell illustrations
Rovalpituzumab tesirine is an antibody drug conjugate with a DNA intercalating agent, which has shown to have an objective response rate of 17% in DLL3 positive patients and an objective response rate of 9% in low DLL3 patients (NCT02709889):diagram 

Of note, rovalpituzumab tesirine is associated with pleural and pericardial effusions.

Dr. Bodei then discussed imaging of neuroendocrine differentiated prostate cancer in vivo with 89Zr-SC16.1 Tumor uptake is significantly higher in the DLL3 positive tumors compared to DLL3 negative tumors, with better visualization with 89Zr-DFO-SC16 compared to 68Ga-PSMA-11 and 68Ga-DOTATE:DLL 3 illustrations
The following two case examples highlights the differences in imaging when targeting DLL3 versus FDG:image-5.jpg
Additionally, Dr. Bodie highlighted that neuroendocrine differentiated prostate cancer lesions also show tumor regression with 177Lu-SC16 therapy:2
As follows are the Kaplan Meier curves for H660 xenografts when treated with various doses of 177Lu-DTPA-SC16:days post treatment
Dr. Morris then provided the final slides, discussing optimization of DLL3 directed therapy, with the following key points:

  1. Develop a next generation Zr-89 radiotracer for DLL3 imaging and a next generation Lu-177 therapeutic for DLL3 theranostic treatment
  2. Demonstrate the ability of 89Zr-MAB1 to image organoid PDX and mouse models expressing varying levels of DLL3
  3. CRISPR screens to identify factors regulating DLL3 expression in CRPC. Dr. Morris and his team will select the top 10-20 genes for further validation in additional cell line models using individual sgRNAs or, if available, small molecule drugs

Dr. Morris and Dr. Bodei concluded their presentation discussing DLL3, a new target for radioligand therapy in neuroendocrine differentiated prostate cancer with the following take home messages:

  • Neuroendocrine differentiated prostate cancer is a substantial healthcare concern in the United States, with 15-20% of mCRPC becoming neuroendocrine differentiated after treatment with ARSIs
  • Prostate cancer is not small cell lung cancer: it is heterogeneous, DLL3 expression has interpatient and intrapatient heterogeneity, imaging will be key to a theranostic approach, and imaging will likely be key to achieving anything other than mediocre responses with other approaches
  • Eligibility criteria for neuroendocrine differentiated prostate cancer trials should be classified by target, rather than the mish-mash of immunohistochemistry, genomic, and other criteria now used. The presence of a target is more important in testing a treatment than other features that have uncertain clinical relevance

Presented by:

  • Michael Morris, Prostate Cancer Section Head, Memorial Sloan Kettering Cancer Center, New York, NY
  • Lisa Bodei, Director of Targeted Radionuclide Therapy, Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 ProsTIC PCF Global Webinar held virtually on July 19, 2023.


  1. Korsen JA, Kalidindi TM, Khitrov S, et al. Molecular imaging of neuroendocrine prostate cancer by targeting Delta-like Ligand 3. J Nucl Med. 2022;63:1401-1407.
  2. Korsen JA, Gutierrez JA, Tully KM, et al. Delta-like ligand 3-targeted radioimmunotherapy for neuroendocrine prostate cancer. PNAS. 2022