CCK2R Biomarker Prediction for Radioligand Therapy Selection
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Solution Overview
Problem
Current methods for predicting the response of cancer patients to treatment and imaging with radiolabeled compounds targeting CCK2-R are hindered by the variability in CCK2-R protein expression levels, leading to inefficient tumor uptake and potential unnecessary radiation exposure, as existing methods for assessing protein expression are unreliable and non-reproducible.
Innovation Solution
The method involves assaying mRNA expression levels of CCKBR in tumor samples to determine if they are above a predetermined cut-off, using a radiolabeled gastrin analogue like X-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2, where X represents a radionuclide chelating moiety such as DOTA, to predict treatment and imaging efficacy, thereby selecting patients likely to benefit from therapy while minimizing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If standard methods (IHC or autoradiography) are used to assess CCK2-R expression levels, then protein expression can be detected, but the results are unreliable and non-reproducible due to method constraints and lack of antibody selectivity
Solution Approach 1:
The patent uses mRNA expression level as an intermediary biomarker to predict CCK2-R protein expression and treatment response. Instead of directly measuring protein expression with unreliable antibodies, the method measures CCKBR mRNA levels which serve as a reliable proxy indicator for predicting both protein expression and radioligand binding potential, thereby resolving the reliability issue of direct protein measurement
Solution Approach 2:
The patent replaces the mechanical/chemical system of antibody-based protein detection (IHC) with a molecular biology-based mRNA detection system. This substitution eliminates the selectivity and specificity problems of available anti-CCK2-R antibodies by using highly specific molecular probes for mRNA detection, achieving more reliable and reproducible results
2Productivity
If radiolabeled compounds are administered to all cancer patients, then treatment coverage is maximized, but unnecessary radiation exposure occurs in patients with low CCK2-R expression
Solution Approach 1:
The patent performs preliminary assessment of CCKBR mRNA expression levels in tumor samples before administering radiolabeled compounds. This preliminary action identifies patients with sufficient receptor expression potential, allowing clinicians to pre-select candidates who are likely to benefit from treatment and avoid unnecessary radiation exposure in patients with low expression levels
Solution Approach 2:
The patent establishes a feedback loop where mRNA expression levels provide predictive information about treatment response. This feedback mechanism allows clinicians to adjust treatment decisions based on predicted efficacy, administering radiolabeled compounds only to patients whose mRNA profiles suggest sufficient CCK2-R expression and likely treatment benefit
3Quantity of substance
If radiolabeled gastrin analogues are used for PRRT, then tumor uptake can be achieved, but uptake efficiency varies significantly due to individual tumor and patient differences in CCK2-R expression
Solution Approach 1:
The patent applies the principle of local quality by assessing mRNA expression levels in the specific tumor tissue of each patient. This localized assessment identifies patients whose tumors have the specific quality of sufficient CCK2-R expression potential, allowing personalized treatment selection that matches the local characteristics of each tumor rather than applying a uniform treatment approach
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach allows for accurate prediction of treatment response and improved tumor uptake of radiolabeled compounds, reducing unnecessary radiation exposure and enhancing therapeutic efficacy by identifying patients with sufficient CCK2-R expression levels, thus optimizing biodistribution and minimizing side effects.
Implementation Method 1
GPCRs targeted by agonistic ligands undergo conformational changes, which lead to the exchange of GDP for GTP on the G-protein alpha subunit (Gα). Subsequent dissociation of the Gα and Gβγ subunits from the receptor results in activation of various kinase signaling pathways... Subsequently, activated GPCRs undergo desensitization via an arrestin-mediated internalization process, whereby they can be trafficked to lysosomes for degradation, or to endosomes for their recycling back to the cell surface. This internalization process enables the delivery of ligand-conjugated radioactive nuclides into target cells, e.g., cancer cells.
Implementation Method 2
X represents a moiety that chelates a radionuclide, preferably DOTA or NODAGA, more preferably DOTA
Data Source
AI summary
A predictive method and a compound for use in treating and/or imaging cancer. The present invention relates to a method for predicting the response of a patient diagnosed with cancer to treatment and/or imaging with a compound targeting cholecystokinin 2 receptor. There is also described a compound targeting CCK2R for use in methods of selectively treating and/or imaging cancer in a patient diagnosed therewith, which leads to improved delivery and therapeutic efficacy and/or enables improved imaging of the tumor tissues.