Cell-free tumor DNA detection for targeted therapy response
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Solution Overview
Problem
Current methods for assessing the efficacy of targeted therapies in cancer, such as kinase inhibitors, are limited by incomplete pharmacological suppression and resistance mutations, and rely on invasive imaging techniques that do not fully represent molecular and pathologic changes in tumors.
Innovation Solution
Developing ultrasensitive methods using targeted and whole genome sequencing approaches to detect cell-free tumor DNA (ctDNA) changes, allowing for rapid assessment of therapeutic responses in advanced lung cancer patients, including detecting genetic alterations and aneuploidy in circulating tumor DNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If CT imaging is used to assess response to targeted therapy, then the method is non-invasive and readily available, but it does not fully represent the molecular and pathologic changes occurring in tumors
Solution Approach 1:
The patent uses cell-free circulating tumor DNA (ctDNA) as an intermediary mediator to bridge the gap between tumor molecular changes and detectable signals. ctDNA serves as a non-invasive proxy that reflects tumor molecular state without requiring tissue biopsy or complex imaging analysis, thus achieving high measurement precision while maintaining operational simplicity
Solution Approach 2:
The patent creates a molecular copy of tumor DNA in the circulating blood (ctDNA) that replicates the tumor's genetic alterations. By sequencing these copies, the method captures molecular tumor characteristics without directly analyzing the tumor itself, enabling precise molecular detection through a simplified blood-based approach
2Loss of time
If traditional CT imaging is used for disease monitoring, then the approach is clinically established, but it cannot detect early molecular responses or resistance changes
Solution Approach 1:
The patent performs preliminary molecular assessment of tumor response by analyzing ctDNA changes that occur early in treatment. This preliminary detection of molecular alterations (such as reduction in tumor-specific mutations or emergence of resistance mutations) happens before structural changes are visible on CT scans, enabling earlier intervention decisions
Solution Approach 2:
The patent replaces the mechanical imaging system (CT scanner) with a molecular analysis system (DNA sequencing). This substitution allows detection of response mechanisms at the molecular level rather than relying on macroscopic structural changes, significantly reducing the time to detect treatment response or resistance
3Measurement precision
If invasive tissue biopsy is performed to assess tumor response, then molecular changes can be directly measured, but the procedure is invasive and complex
Solution Approach 1:
The patent uses circulating ctDNA as an intermediary that carries tumor molecular information without requiring direct tumor tissue sampling. This intermediary approach maintains the molecular analysis precision of biopsies while eliminating the invasiveness, as blood draws are simple and non-invasive compared to tissue biopsies
Solution Approach 2:
The patent obtains a copy of tumor DNA through the circulation of ctDNA in blood rather than directly extracting tumor tissue. This copying approach preserves the molecular genetic information needed for precise tumor analysis while using a simple, non-invasive blood sampling method instead of complex tissue biopsy procedures
Data Source
AI summary
Provided herein are method of determining the efficacy of targeted therapy in a subject by detecting changes in levels of cell-free tumor load (cfTL). In some aspects, the efficacy of targeted therapy is determined a very short time after the targeted therapy is administered. Also provided herein are method of determining resistance to a targeted therapy in a subject by detecting changes in levels of cell-free tumor load (cfTL).