Templated Insertion Biomarkers for HRD Cancer Treatment Selection
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Solution Overview
Problem
There is an urgent need for reliable and accurate methods to predict whether a cancer patient with homologous recombination deficiency (HRD) will benefit from treatment with PARP inhibitors or platinum agents, as current treatments have limited effectiveness in advanced epithelial ovarian cancers.
Innovation Solution
The method involves detecting elevated levels of templated insertions (TINS), including direct-repeat TINS (drTINS) and inverted TINS (iTINS), in a cancer patient's biological sample compared to a healthy control or predetermined threshold, and administering an effective amount of a PARP inhibitor or platinum agent based on these findings.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PARP inhibitors or platinum agents are administered to all HRD cancer patients, then some patients may benefit from treatment, but many patients will not respond and will experience unnecessary side effects
Solution Approach 1:
The patent applies preliminary action by detecting templated insertion signatures in tumor DNA before administering PARP inhibitors or platinum agents. This pre-treatment genetic screening identifies patients with specific HRD characteristics (elevated TINS, drTINS, or iTINS signatures) who are most likely to respond to therapy, allowing clinicians to prescribe these drugs only to pre-selected patients rather than all HRD patients, thereby avoiding unnecessary side effects in non-responders.
2Productivity
If current platinum-based chemotherapy is used as standard of care, then initial treatment response is achieved, but nearly all stage III and all stage IV cancers recur
Solution Approach 1:
The patent applies feedback by using templated insertion signature detection as a biomarker to guide treatment decisions. The presence or absence of specific TINS signatures provides feedback about a patient's HRD status and predicted treatment response, enabling clinicians to select patients most likely to benefit from PARP inhibitors or platinum agents. This feedback mechanism aims to improve durable response and overall survival by avoiding treatment of patients unlikely to respond, addressing the recurrence problem in advanced stages.
3Measurement precision
If genetic screening methods are developed to predict treatment response, then treatment selection accuracy improves, but the complexity of diagnostic procedures increases
Solution Approach 1:
The patent applies the taking out principle by extracting and focusing on a specific, targeted genetic feature (templated insertion signatures) rather than performing comprehensive genomic analysis. By detecting only TINS, drTINS, or iTINS signatures in tumor DNA, the method achieves predictive accuracy while simplifying the diagnostic procedure compared to whole-genome sequencing or analysis of multiple genetic markers, thus reducing diagnostic complexity while maintaining measurement precision.
Data Source
AI summary
The present disclosure provides methods for determining whether a cancer patient with homologous recombination deficiency will benefit from treatment with PARP inhibitors or platinum agents. These methods are based on screening a cancer patient for the presence of templated insertions (TINS), including direct-repeat templated insertions (drTINS) and inverted templated insertions (iTINS).