Dataset Information

Examining the Feasibility of Quantifying Receptor Availability Using Cross-Modality Paired-Agent Imaging.

ABSTRACT:

Purpose

The ability to noninvasively quantify receptor availability (RA) in solid tumors is an aspirational goal of molecular imaging, often challenged by the influence of non-specific accumulation of the contrast agent. Paired-agent imaging (PAI) techniques aim to compensate for this effect by imaging the kinetics of a targeted agent and an untargeted isotype, often simultaneously, and comparing the kinetics of the two agents to estimate RA. This is usually accomplished using two spectrally distinct fluorescent agents, limiting the technique to superficial tissues and/or preclinical applications. Applying the approach in humans using conventional imaging modalities is generally infeasible since most modalities are unable to routinely image multiple agents simultaneously. We examine the ability of PAI to be implemented in a cross-modality paradigm, in which the targeted and untargeted agent kinetics are imaged with different modalities and used to recover receptor availability.

Procedures

Eighteen mice bearing orthotopic brain tumors were administered a solution containing three contrast agents: (1) a fluorescent agent targeted to epidermal growth factor receptor (EGFR), (2) an untargeted fluorescent isotype, and (3) a gadolinium-based contrast agent (GBCA) for MRI imaging. The kinetics of all three agents were imaged for 1 h after administration using an MRI-coupled fluorescence tomography system. Paired-agent receptor availability was computed using (1) the conventional all-optical approach using the targeted and untargeted optical agent images and (2) the cross-modality approach using the targeted optical and untargeted MRI-GBCA images. Receptor availability estimates between the two methods were compared.

Results

Receptor availability values using the cross-modality approach were highly correlated to the conventional, single-modality approach (r = 0.94; p < 0.00001).

Conclusion

These results suggest that cross-modality paired-agent imaging for quantifying receptor availability is feasible. Ultimately, cross-modality paired-agent imaging could facilitate rapid, noninvasive receptor availability quantification in humans using hybrid clinical imaging modalities.

SUBMITTER: Meng B

PROVIDER: S-EPMC8760219 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immuno-oncological treatment strategies that target abnormal receptor profiles of tumors are an increasingly important feature of cancer therapy. Yet, assessing receptor availability (RA) and drug-target engagement, important determinants of therapeutic efficacy, is challenging with current imaging strategies, largely due to the complex nonspecific uptake behavior of imaging agents in tumors. Herein, we evaluate whether a quantitative noninvasive imaging approach designed to compensate for nonspecific uptake, MRI-coupled paired-agent fluorescence tomography (MRI-PAFT), is capable of rapidly assessing the availability of epidermal growth factor receptor (EGFR) in response to one dose of anti-EGFR antibody therapy in orthotopic brain tumor models. Methods: Mice bearing orthotopic brain tumor xenografts with relatively high EGFR expression (U251) (N=10) or undetectable human EGFR (9L) (N=9) were considered in this study. For each tumor type, mice were either treated with one dose of cetuximab, or remained untreated. All animals were scanned using MRI-PAFT, which commenced immediately after paired-agent administration, and values of RA were recovered using a model-based approach, which uses the entire dynamic sequence of agent uptake, as well as a simplified "snapshot" approach which requires uptake measurements at only two time points. Recovered values of RA were evaluated between groups and techniques. Hematoxylin & eosin (H&E) and immunohistochemical (IHC) staining was performed on tumor specimens from every animal to confirm tumor presence and EGFR status. Results: In animals bearing EGFR(+) tumors, a significant difference in RA values between treated and untreated animals was observed (RA = 0.24 ± 0.15 and 0.61 ± 0.18, respectively, p=0.027), with an area under the curve - receiver operating characteristic (AUC-ROC) value of 0.92. We did not observe a statistically significant difference in RA values between treated and untreated animals bearing EGFR(-) tumors (RA = 0.18 ± 0.19 and 0.27 ± 0.21, respectively; p = 0.89; AUC-ROC = 0.55), nor did we observe a difference between treated EGFR(+) tumors compared to treated and untreated EGFR(-) tumors. Notably, the snapshot paired-agent strategy quantified drug-receptor engagement within just 30 minutes of agent administration. Examination of the targeted agent alone showed no capacity to distinguish tumors either by treatment or receptor status, even 24h after agent administration. Conclusions: This study demonstrated that a noninvasive imaging strategy enables rapid quantification of receptor availability in response to therapy, a capability that could be leveraged in preclinical drug development, patient stratification, and treatment monitoring.