title: Tumor-selective anti-cancer effects of the synthetic alkyl phosphocholine analog CLR1404 in neuroblastoma.
abstract: Neuroblastoma (NB) is the most common extracranial solid tumor in children and is associated with high mortality in advanced stages. Survivors suffer from long-term treatment-related sequelae. Thus, new targeted treatment options are urgently needed. 18-(p-[(127)I] iodophenyl) octadecyl phosphocholine (CLR1404) is a novel, broadly tumor targeted small molecule drug suitable for intravenous injection with highly selective tumor uptake. As a carrier molecule for radioactive iodine, CLR1404 is in clinical trials as cancer imaging agent and radiotherapeutic drug. Chemically, CLR1404 belongs to the anti-tumor alkyl phospholipids, a class of drugs known to have intrinsic cytotoxic effects on cancer cells. Therefore, we hypothesized that CLR1404 could be a tumor-targeted anti-cancer agent for neuroblastoma, and investigated its effect in vitro and in vivo. CLR1404 was taken up by NB cells in a highly tumor-selective manner both in vitro and in vivo, confirmed by flow cytometry and PET/CT imaging of mouse flank xenografts with (124)I-CLR1404, respectively. Using flow cytometry, MTT assay, Western blotting and caspase 3/7 assay, we confirm that in vitro treatment with CLR1404 leads to robust apoptosis and cell death in multiple NB cell lines and is associated with Akt inhibition, while sparing normal cells. Treatment with CLR1404 in doses of 10 or 30 mg/kg administered by intravenous injection once weekly for 7 weeks significantly inhibited the tumor growth rate in a mouse flank xenograft model of NB (P<0.001) when compared to control cohorts, without causing drug-related hematotoxicity or other noticeable adverse effects, which was determined by serial tumor volume measurements, complete blood counts, and monitoring of animal-specific health parameters. We conclude that CLR1404 warrants clinical exploration as a novel, tumor selective anticancer agent in NB and potentially other cancers.
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Marino
authors.affiliation: Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Baiu
authors.affiliation: Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Saswati
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Cellectar Biosciences 3301 Agriculture Drive, Madison, WI 53716, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Titz
authors.affiliation: Department of Medicine, University of Wisconsin-Madison 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hebron
authors.affiliation: Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Menapace
authors.affiliation: Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Sorabh
authors.initials: S
authors.lastname: Singhal
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison 600 Highland Avenue, Madison, WI 53792, USA.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.affiliation: Department of Medicine, University of Wisconsin-Madison 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Fotis
authors.initials: F
authors.lastname: Asimakopoulos
authors.affiliation: Cellectar Biosciences3301 Agriculture Drive, Madison, WI 53716, USA; Departments of Radiology and Medical Physics, University of Wisconsin-Madison School of Medicine and Public Health1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Jamey P
authors.initials: JP
authors.lastname: Weichert
authors.affiliation: Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Otto
keywords: Akt; CLR1404; Neuroblastoma; alkyl phosphocholine analog; alkyl phospholipid; pediatric cancer; targeted therapy