Topoisomerase I Phosphorylation Marker for Chemosensitivity Prediction
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Solution Overview
Problem
Current cancer chemotherapy methods are inefficient in predicting the response of cancer patients to topoisomerase I inhibitors, as existing methods are poor predictors of chemosensitivity, time-consuming, and costly, and do not effectively address resistance to topo I inhibitors in cancers such as breast, lung, ovarian, brain, colon, and prostate cancers.
Innovation Solution
A diagnostic marker is developed to predict the efficacy of topoisomerase I inhibitors by detecting the phosphorylation of topo I on serine 10 (S10), which indicates the degradation rate of topo I and resistance to topo I inhibitors like camptothecin and its analogues, using methods such as immunohistochemistry and computer-based systems to determine the phosphorylation status in biological samples.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If in vitro or ex vivo testing of tumor cells to a battery of drugs is used to predict chemosensitivity, then treatment individualization is improved, but the process becomes time-consuming and costly
Solution Approach 1:
The patent extracts the predictive marker function from complex in vitro drug testing batteries and isolates it to a single measurable parameter - the ratio of phosphorylated to total topoisomerase I protein. This extraction allows chemosensitivity prediction without requiring time-consuming multi-drug testing protocols, directly resolving the contradiction between reliable prediction and time consumption.
Solution Approach 2:
The patent changes the measurement parameter from functional drug response testing to a molecular marker ratio (phosphorylated topo I / total topo I). This parameter transformation enables rapid prediction of chemosensitivity without replicating the full drug testing process, thereby reducing time while maintaining predictive reliability.
2Reliability
If in vitro or ex vivo testing of tumor cells to a battery of drugs is used to predict chemosensitivity, then treatment individualization is improved, but the process becomes costly
Solution Approach 1:
The patent extracts the predictive function from expensive multi-drug testing batteries and concentrates it into a single molecular marker measurement. By taking out only the essential predictive information (topo I phosphorylation status) rather than testing all drugs, the cost is dramatically reduced while maintaining prediction reliability.
Solution Approach 2:
The patent replaces expensive, time-consuming drug testing kits with a cheaper, rapid molecular detection method. The disposable nature of the phosphorylation marker detection allows for low-cost repeated testing without requiring expensive reagents or specialized testing infrastructure for each measurement.
3Ease of operation
If topoisomerase I protein level is measured to predict response to topo I inhibitors, then the marker is simple to detect, but the marker is not useful because topo I levels are high in most solid tumors and do not provide prognostic index
Solution Approach 1:
The patent applies local quality by focusing not on the global quantity of topoisomerase I (which is uniformly high in most tumors), but on the specific local property of phosphorylation at serine 10. This localized modification creates a distinguishable state that correlates with drug response, enabling reliable prediction while maintaining ease of detection through phosphorylation-specific antibodies.
Solution Approach 2:
The patent changes the measurement from total protein quantity to phosphorylation status. This parameter transformation creates a binary or graded scale (phosphorylated vs. non-phosphorylated) that provides clear prognostic information, resolving the issue where total topo I levels were non-discriminatory despite being easy to detect.
4Reliability
If manual testing methods are used to evaluate tumor sensitivity, then comprehensive drug testing is possible, but the process becomes manually intensive and expensive
Solution Approach 1:
The patent replaces manual mechanical drug testing procedures with an automated molecular detection system. By substituting the manual battery of drug tests with an automated immunoassay for phosphorylated topoisomerase I, the system reduces manual intensity while maintaining comprehensive evaluation capability through objective molecular measurement.
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 personalized treatment by identifying patients likely to be responsive or non-responsive to topo I inhibitors, enabling more effective treatment strategies and reducing toxicity, particularly in refractory cancer types.
Implementation Method 1
topoI is phosphorylated at S10 by DNA-PK and results in its ubiquitination by BRAC1/BARD1 heterodimer and its subsequent degradation
Implementation Method 2
topoI is phosphorylated at S10 by DNA-PK and results in its ubiquitination by BRAC1/BARD1 heterodimer and its subsequent degradation
Implementation Method 3
it has been demonstrated that topoI is ubiquitinated and degraded in cells in the response to CPT by ubiquitin proteosomal pathway (UPP)
Data Source
Figure 1A~1C
Figure 1D~1E
Figure 2A~2C
AI summary
The present invention generally relates to the fields of cancer therapy and cancer prevention. More particularly, the present invention generally relates to a diagnostic marker for predicting the efficacy of topoisomerase I (topo I) inhibitors in the treatment of cancers. More specifically, the present invention relates to methods, machines, computer systems, computable readable media and kits which can be used to identify and determine the effectiveness of topoisomerase I (topo I) inhibitors in the treatment of cancers, and in some embodiments, the level of sensitivity or resistance of a tumor cell to a topoisomerase I inhibitor, such as camptothecin (CPT), or CTP analogues such as topotecan and irinotecan and derivatives thereof. More specifically, the present invention related to methods, machines, computer systems, computable readable media and kits which can be used to determine the presence of phosphorylation of topoisomerase I polypeptide, in some embodiments phosphorylation at residue serine 10 (S10) of a topoisomerase I polypeptide, wherein the presence of phosphorylation, in particular the phosphorylation at serine 10 of a topoI polypeptide indicates a cancer is likely to be unresponsive to a topo I inhibitor, whereas the absence of phosphorylation, in particular, the absence of phosphorylation at residue serine 10 (S10) identifies a cancer is likely to be responsive to a topo I inhibitor. Other aspect of the present invention relate to phospho-serine10 topoisomerase I antibodies and other protein binding moieties, and uses thereof.