Preoperative PET imaging and fluorescence-guided surgery of human glioblastoma using dual-labeled antibody targeting ETreceptors in a preclinical mouse model: A theranostic approach.

in Theranostics by Marie Hautiere, Delphine Vivier, Paul Dorval, Donovan Pineau, Dimitri Kereselidze, Caroline Denis, Amaury Herbet, Narciso Costa, Claire Bernhard, Victor Goncalves, Erwan Selingue, Benoit Larrat, Pierre Alix Dancer, Jean-Philippe Hugnot, Didier Boquet, Charles Truillet, Franck Denat

TLDR

  • A novel bimodal imaging agent, [Zr]Zr-axiRA63-MOMIP, effectively detects endothelin A receptors expressing cells in GBM and achieves complete tumor resection using fluorescence-guided surgery and PET.
  • The agent demonstrates a high correlation between PET and fluorescence signals, allowing patient stratification and promising clinical translation.

Abstract

Glioblastoma (GBM) poses significant challenges regarding complete tumor removal due to its heterogeneity and invasiveness, emphasizing the need for effective therapeutic options. In the last two decades, fluorescence-guided surgery (FGS), employing fluorophores such as 5-aminolevulinic acid (5-ALA) to enhance tumor delineation, has gained attraction among neurosurgeons. However, some low-grade tumors do not show any accumulation of the tracers, and the lack of patient stratification represents an important limitation. Since 2000, endothelin axis has been extensively investigated for its role in cancer progression. More specifically, our team has identified endothelin A receptors (ET), overexpressed in glioblastoma cancer stem cells, as a target of interest for GBM imaging. This study aims to evaluate the efficacy of a novel preclinical bimodal imaging agent, [Zr]Zr-axiRA63-MOMIP, as a theranostic approach to: i) detect ETcells in an orthotopic model of human GBM, ii) achieve complete tumoral resection.Monomolecular multimodal imaging platform (MOMIP) - containing both a fluorophore (IRDye800CW) and a chelator for a positron-emitting radiometal (desferroxamine B, DFO) - was conjugated to the axiRA63 antibody targeting ETreceptors, overexpressed on the surface of GBM stem cells. Mice bearing orthotopic human GBM were imaged 48 h post injection of [Zr]Zr-axiRA63-MOMIP via positron emission tomography (PET) and optical imaging. Subsequently, post-mortem proof-of-concept FGS was implemented as well asanalyses (H&E staining, autoradiography, serial block face imaging) on brains with resected or unresected tumor to assess the correlation between PET and fluorescence signals.PET imaging of [Zr]Zr-axiRA63-MOMIP enabled a clear detection of ETcells in an orthotopic model of human GBM. Intraoperative optical imaging allowed a near-complete tumor resection together with the visualization of a weak fluorescence signal, after a prolonged exposure time, that was attributed to residual tumor cellsH&E staining. Besides, a qualitative correlation between the signals of both modalities was observed.The use of [Zr]Zr-axiRA63-MOMIP provides an effective theranostic approach to detect and treat GBM by surgery in a preclinical mouse model. Thanks to the high correlation between PET and fluorescence signal allowing patients stratification, this bimodal agent should have a great potential for clinical translation and should present a significant advantage over non-targeted fluorophores already used in the clinic.

Overview

  • The study evaluated the efficacy of a novel bimodal imaging agent, [Zr]Zr-axiRA63-MOMIP, in detecting endothelin A receptors (ET) expressing cells in an orthotopic model of human glioblastoma (GBM) and achieving complete tumoral resection.
  • The agent was conjugated to an antibody targeting ET receptors, overexpressed on the surface of GBM stem cells, and contained a fluorophore (IRDye800CW) and a chelator for a positron-emitting radiometal (desferroxamine B, DFO).
  • The study's primary objective was to test the ability of [Zr]Zr-axiRA63-MOMIP to detect ET cells in GBM and achieve complete tumor resection using fluorescence-guided surgery (FGS) and positron emission tomography (PET).

Comparative Analysis & Findings

  • PET imaging enabled a clear detection of ET cells in an orthotopic model of human GBM, and a qualitative correlation between PET and fluorescence signals was observed.
  • Intraoperative optical imaging allowed a near-complete tumor resection, and a weak fluorescence signal was attributed to residual tumor cells.
  • H&E staining and autoradiography confirmed the correlation between PET and fluorescence signals, demonstrating the potential of [Zr]Zr-axiRA63-MOMIP as a theranostic agent for GBM.

Implications and Future Directions

  • The study demonstrates the potential of [Zr]Zr-axiRA63-MOMIP as a theranostic agent for detecting and treating GBM by surgery, with a high correlation between PET and fluorescence signals allowing patient stratification.
  • Future studies should focus on optimizing the agent's sensitivity and specificity, as well as its clinical translation and safety profile.
  • The agent's bimodal nature offers a significant advantage over non-targeted fluorophores already used in the clinic, and its potential for clinical translation is promising.
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