BCR-ABL1 Splice Variant Detection for CML Resistance Prediction
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current kinase inhibitors, such as imatinib, face significant challenges in effectively treating Chronic Myelogenous Leukemia (CML) due to resistance mechanisms, including alternative bcr-abl1 splice variants that confer resistance to treatment, with unclear mechanisms and limited understanding of resistance mechanisms beyond mutations in the bcr-abl1 gene.
Innovation Solution
The development of methods to predict resistance to BCR-ABL1 kinase inhibitors by assessing for the presence of specific bcr-abl1 splice variants, such as the 195INS and 243INS variants, through nucleic acid sequencing and protein detection, allowing for personalized treatment approaches and identification of drug candidates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If kinase inhibitors such as imatinib are used to treat CML, then treatment effectiveness is improved, but resistance develops due to alternative bcr-abl1 splice variants
Solution Approach 1:
The patent applies preliminary action by detecting alternative bcr-abl1 splice variants (such as 195INS and 243INS variants) before initiating kinase inhibitor treatment. This allows clinicians to identify patients at risk of developing resistance and select alternative treatment strategies or combination therapies in advance, preventing treatment failure before it occurs.
Solution Approach 2:
The patent applies parameter changes by altering the treatment approach based on the detected splice variant profile. When alternative splice variants are identified, the treatment parameters are changed from standard kinase inhibitor monotherapy to alternative regimens, thereby adapting the treatment to the specific molecular characteristics of the patient's disease.
2Productivity
If standard kinase inhibitor therapy is administered, then initial response is achieved, but secondary resistance occurs leading to hematologic recurrence
Solution Approach 1:
The patent applies feedback by using the detection of alternative bcr-abl1 splice variants as a monitoring mechanism during treatment. This feedback information allows clinicians to assess whether the current kinase inhibitor therapy is likely to maintain long-term effectiveness or if resistance is developing, enabling timely intervention to prolong treatment duration and prevent recurrence.
3Measurement precision
If monitoring for bcr-abl1 mutations is performed, then resistance mechanisms are identified, but alternative splice variants remain undetected
Solution Approach 1:
The patent applies universality by developing a comprehensive detection method that simultaneously identifies both traditional bcr-abl1 mutations and alternative splice variants (such as 195INS and 243INS variants) using a single diagnostic approach. This multi-functional detection system ensures that all major resistance mechanisms are captured, providing a complete picture of the resistance landscape.
Data Source
AI summary
The present invention is based on BCR-ABL1 splice variants which result from insertion and/or truncation of the bcr-abl1 transcript and the finding that these variants provide resistance to kinase domain inhibitors such as imatinib, nilotinib and dasatinib.