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 as 90Y. 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 with 90Y-DOTA-AR with or without VTP. The uptake of radioisotopes was monitored by Cherenkov luminescence Imaging (CLI). The therapeutic efficacy of the combined VTP and 90Y-DOTA-AR in PC-3 xenografts was assessed. Results CLI of 90Y-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) post 90Y-DOTA-AR injection. A similar pattern of retention was observed in VCaP xenografts. When 90Y-DOTA-AR administration was combined with VTP, tumor growth delay was significantly longer than for the control or the mono-therapy groups. Conclusions Tumor vascular arrest by VTP improves 90Y-DOTA-AR retention in the tumor microenvironment thereby enhancing therapeutic efficacy.

Potentiating vascular-targeted photodynamic therapy through CSF-1R modulation of myeloid cells in a preclinical model of prostate cancer

“…We also observed a considerable reduction in the number of CD11b + cells, including neutrophils and MDSCs in the tumor, when mice were given anti-CSF1R antibody alone or in combination with VTP ( Figure 3(f-h)). Finally, our group has previously shown that VTP obliterates the tumor vasculature in PC-3 xenografts immediately post-VTP treatment 35 and we wanted to determine if combining anti-CSF 1R with VTP therapy had any effect on the vasculature at later time points. However, we found that while the vasculature in VTPtreated tumors mostly recovered by day 10 after therapy, combining anti-CSF1R to VTP therapy had modest to little effect, which contrasted with a greater increase in vasculature in the tumors only receiving anti-CSF1R ( Supplementary Figure 7).…”

Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist 177Lu‐DOTAGA‐PEG2‐RM26

“…The above GRPR-antagonist was coupled with the DOTA chelator via different linkers and labeled with therapeutic radiometals, such as lutetium-177 2,28 or yttrium-90. 29 In all studies, a significant delay of tumor growth was observed in animals treated with the radiopeptide. In the present work, we have modified the same GRPR-antagonist RM26 by coupling triand tetra-aza macrocyclic chelators to its N-terminus via a PEG 2 -linker and investigated the respective 177 Lu-labeled radiopeptides for their efficacy in GRPR-targeted radiotherapy of prostate cancer in preclinical models.…”

“…Analogs of the GRPR‐antagonist [D‐Phe 6 ,Sta 13 ,Leu 14 ‐NH 2 ]bombesin(6–14) recently attracted attention as new molecular tools for TRT of prostate cancer. The above GRPR‐antagonist was coupled with the DOTA chelator via different linkers and labeled with therapeutic radiometals, such as lutetium‐177 or yttrium‐90 . In all studies, a significant delay of tumor growth was observed in animals treated with the radiopeptide.…”

Partial ablation versus radical prostatectomy in intermediate-risk prostate cancer: the PART feasibility RCT

“…31 Recently, a manufacturer-sponsored Phase III RCT comparing VTP with AM in 413 men with very low-risk disease has been published with 2-year follow-up data. 20 It found VTP to be safe and effective, with a 66% reduced risk of treatment failure (adjusted hazard ratio 0.34, 95% confidence interval 0.24 to 0.46) compared with AM; however, the VTP group experienced more frequent and severe side effects, although these were mostly mild and of short duration. The most common side effect was difficulty passing urine, and in all cases this resolved within 2 months of treatment.…”

“…[17][18][19] A manufacturer-sponsored Phase III RCT of VTP versus AM in 413 men with very low-risk disease has been published recently with 2-year follow-up data. 20 This is discussed below.…”