title: Bombesin Antagonist-Based Radiotherapy of Prostate Cancer Combined with WST-11 Vascular Targeted Photodynamic Therapy.
abstract: Purpose:DOTA-AR, a bombesin-antagonist peptide, has potential clinical application for targeted imaging and therapy in gastrin-releasing peptide receptor (GRPr)-positive malignancies when conjugated with a radioisotope such as90Y. This therapeutic potential is limited by the fast washout of the conjugates from the target tumors. WST-11 (Weizmann STeba-11 drug; a negatively charged water-soluble palladium-bacteriochlorophyll derivative, Tookad Soluble) vascular targeted photodynamic therapy (VTP) is a local ablation approach recently approved for use in early-stage prostate cancer. It generates reactive oxygen/nitrogen species within tumor blood vessels, resulting in their instantaneous destruction followed by rapid tumor necrosis. We hypothesize that the instantaneous arrest of tumor vasculature may provide a means to trap radiopharmaceuticals within the tumor, thereby improving the efficacy of targeted radiotherapy.Experimental Design:GRPr-positive prostate cancer xenografts (PC-3 and VCaP) were treated with90Y-DOTA-AR with or without VTP. The uptake of radioisotopes was monitored by Cherenkov luminescence imaging (CLI). The therapeutic efficacy of the combined VTP and90Y-DOTA-AR in PC-3 xenografts was assessed.Results:CLI of90Y-DOTA-AR demonstrated longer retention of radiotracer within the VTP-treated PC-3 xenografts compared with the non-VTP-treated ones (P< 0.05) at all time points (24-144 hours) after90Y-DOTA-AR injection. A similar pattern of retention was observed in VCaP xenografts. When90Y-DOTA-AR administration was combined with VTP, tumor growth delay was significantly longer than for the control or the monotherapy groups.Conclusions:Tumor vascular arrest by VTP improves90Y-DOTA-AR retention in the tumor microenvironment thereby enhancing therapeutic efficacy.Clin Cancer Res; 23(13); 3343-51. ©2017 AACR.
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Kwanghee
authors.initials: K
authors.lastname: Kim
authors.affiliation: Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Stephen
authors.initials: S
authors.lastname: La Rosa
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Jebiwott
authors.affiliation: Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Pooja
authors.initials: P
authors.lastname: Desai
authors.affiliation: Urology, Palo Alto Medical Foundation, Stanford, California.
authors.forename: Simon
authors.initials: S
authors.lastname: Kimm
authors.affiliation: Plant Science, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Avigdor
authors.initials: A
authors.lastname: Scherz
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: O'Donoghue
authors.affiliation: Molecular Imaging and Therapy Services, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Weber
authors.affiliation: Division of Urology, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York. colemanj@mskcc.org.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coleman
mesh_terms: D000818:Animals; D001429:Bacteriochlorophylls / Q000008:administration & dosage; D001839:Bombesin / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D008297:Male; D051379:Mice; D010455:Peptides / Q000008:administration & dosage*; D010778:Photochemotherapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D011868:Radioisotopes / Q000008:administration & dosage; D014018:Tissue Distribution / Q000187:drug effects / Q000528:radiation effects; D059016:Tumor Microenvironment / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001429:Bacteriochlorophylls; D010455:Peptides; D011868:Radioisotopes; C503696:padeliporfin; D001839:Bombesin