Delta-like Ligand 3 (DLL3) is a novel target for molecular imaging of Neuroendocrine Prostate Cancer
JOURNAL OF NUCLEAR MEDICINE(2020)
Abstract
133 Objectives: Transdifferentiation of prostate adenocarcinoma to Neuroendocrine Prostate Cancer (NEPC) has emerged as one of the leading causes of resistance to androgen deprivation therapy (ADT) [1]. The patients have aggressive disease with visceral metastasis and have short survival time (7-10 months) [2]. Genomic and proteomic characterization of biopsy samples of NEPC lesions indicates loss of androgen receptor (AR) signaling [3]. Therefore, current PET imaging agents such as 18F-FDHT and 68Ga-PSMA11 that rely on functional AR cannot be used. Our goal is to develop a PET based molecular imaging agent that can uniquely identify NEPC lesions. Taking advantage of highly specific expression of Delta-like ligand 3 (DLL3) in NEPC lesions, we have developed zirconium-89 labeled immunoPET agent that can specifically identify NEPC lesions. Methods: We have used well characterized NCI-H660 cell line as representative NEPC model and compared it with AR dependent LNCaP and AR independent PC3 and DU145 cell lines. qPCR was used to measure relative levels of AR-regulated gene transcripts (AR, PSMA, PSA) and NEPC marker DLL3 and normalized to β-actin in the cell lines. Relative protein levels of AR regulated genes and DLL3 were measured by western blot analysis of cellular extracts using β-actin as our control. ImmunoPET agent - 89Zr-SC16 - was developed through the conjugation of the DFO chelator to SC16 (DLL3 specific) mAb and radiolabeled with zirconium-89. Saturation binding assay was performed on the cell line NCI-H660 to determine Bmax and Kd values. For in vivo PET imaging and biodistribution studies, NCI-H660 (DLL3/+) or DU145 (DLL3/-) xenografts were established in 6-8 week old male athymic nude mice. The mice were administered with 89Zr-SC16 and imaged at 24, 48, 72, 96, and 120 h post injection on a PET scanner and at chosen time points mice were euthanized and organs collected for biodistribution studies. Results: Saturation binding assay reveals that Kd =0.35 nM and Bmax = 863 fm/106 cells for 89Zr-SC16. In vitro studies indicated that NCI-H660 cell line was positive for DLL3 and negative for AR, PSA, and PSMA both at transcriptional and translational level. As expected all other cells except PC3 were negative for DLL3. Invivo PET imaging with 89Zr-SC16 showed clear delineation of NCI-H660 (DLL3/+) tumor xenografts. Biodistribution studies showed tumor uptake of 18.4 ± 3.8 %ID/g in the NCI-H660 tumors compared to 5.5 ± 0.5 %ID/g in the DU145 tumors, demonstrating the selective accumulation of the radiotracer in the DLL3-expressing tumors. Conclusions: Our findings demonstrate that only NEPC cells selectively express DLL3 and using DLL3 targeting PET agent 89Zr-SC16 we can non-invasively and uniquely identify NEPC lesions in vivo. Acknowledgement: Partial funding for these studies was provided by 2019 Geoffrey Beene Cancer Research Center Grant.
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Key words
PET Imaging,Metastatic Prostate Cancer,Prostate Cancer,Alpha Particle Therapy
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