Generalized paired-agent kinetic model for in vivo quantification of cancer cell-surface receptors under receptor
N Sadeghipour1, S C Davis2, K M Tichauer1
1Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616, USA.
Abstract:
New precision medicine drugs oftentimes act through binding to specific cell-surface cancer receptors, and thus their efficacy is highly dependent on the availability of those receptors and the receptor concentration per cell. Paired-agent molecular imaging can provide quantitative information on receptor status in vivo, especially in tumor tissue; however, to date, published approaches to paired-agent quantitative imaging require that only 'trace' levels of imaging agent exist compared to receptor concentration. This strict requirement may limit applicability, particularly in drug binding studies, which seek to report on a biological effect in response to saturating receptors with a drug moiety. To extend the regime over which paired-agent imaging may be used, this work presents a generalized simplified reference tissue model (GSRTM) for paired-agent imaging developed to approximate receptor concentration in both non-receptor-saturated and receptor-saturated conditions. Extensive simulation studies show that tumor receptor concentration estimates recovered using the GSRTM are more accurate in receptor-saturation conditions than the standard simple reference tissue model (SRTM) (% error (mean ± sd): GSRTM 0 ± 1 and SRTM 50 ± 1) and match the SRTM accuracy in non-saturated conditions (% error (mean ± sd): GSRTM 5 ± 5 and SRTM 0 ± 5). To further test the approach, GSRTM-estimated receptor concentration was compared to SRTM-estimated values extracted from tumor xenograft in vivo mouse model data. The GSRTM estimates were observed to deviate from the SRTM in tumors with low receptor saturation (which are likely in a saturated regime). Finally, a general 'rule-of-thumb' algorithm is presented to estimate the expected level of receptor saturation that would be achieved in a given tissue provided dose and pharmacokinetic information about the drug or imaging agent being used, and physiological information about the tissue. These studies suggest that the GSRTM is necessary when receptor saturation exceeds 20% and highlight the potential for GSRTM to accurately measure receptor concentrations under saturation conditions, such as might be required during high dose drug studies, or for imaging applications where high concentrations of imaging agent are required to optimize signal-to-noise conditions. This model can also be applied to PET and SPECT imaging studies that tend to suffer from noisier data, but require one less parameter to fit if images are converted to imaging agent concentration (quantitative PET/SPECT).
Insights
A new generalized simplified reference tissue model (GSRTM) accurately estimates cancer receptor concentration, even when receptors are saturated. This advance is crucial for precision medicine drug studies and quantitative molecular imaging.
Area of Science:
- Molecular Imaging and Precision Medicine
- Quantitative Analysis of Biological Receptors
Background:
- Precision medicine drugs target cell-surface cancer receptors, making receptor availability critical for efficacy.
- Current paired-agent molecular imaging methods for receptor status require low imaging agent concentrations, limiting applications like drug binding studies.
Purpose of the Study:
- To develop a generalized simplified reference tissue model (GSRTM) for paired-agent imaging applicable to both non-receptor-saturated and receptor-saturated conditions.
- To extend the utility of quantitative imaging beyond trace-level imaging agent concentrations.
Main Methods:
- Development of the generalized simplified reference tissue model (GSRTM).
- Extensive simulation studies to compare GSRTM with the standard simple reference tissue model (SRTM) under varying receptor saturation levels.
- Validation using in vivo mouse tumor xenograft data comparing GSRTM and SRTM estimates.
- Development of a 'rule-of-thumb' algorithm to estimate receptor saturation levels.
Main Results:
- GSRTM provides more accurate tumor receptor concentration estimates than SRTM under receptor-saturation conditions (0% ± 1% error vs. 50% ± 1% error).
- GSRTM accuracy matches SRTM in non-saturated conditions (5% ± 5% error vs. 0% ± 5% error).
- In vivo data showed GSRTM estimates deviating from SRTM in tumors likely experiencing receptor saturation.
- GSRTM is recommended for use when receptor saturation exceeds 20%.
Conclusions:
- The GSRTM accurately measures receptor concentrations under saturation conditions, essential for high-dose drug studies and optimizing signal-to-noise in molecular imaging.
- This model enhances quantitative PET and SPECT imaging by providing accurate measurements even with noisier data.
- The developed algorithm aids in predicting receptor saturation levels for experimental design.
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