Targeting MASAs via Spliceosome Mutations
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Solution Overview
Problem
Current cancer therapies lack effective targets for various genetic alterations in breast cancer, as most mutations occur in only a few percent of cases, complicating research and clinical trials, and there is an unmet need to find new drivers of cancer that can be therapeutically targeted.
Innovation Solution
The method involves engineering isogenic cell lines to express mutated spliceosome proteins, such as SF3B1, which cause mis-splicing of RNA, leading to the identification and enrichment of mis-splicing-associated surface antigens (MASAs), and using these antigens as targets for therapeutic intervention.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional cancer therapy approaches are used, then existing treatments can be applied, but they lack effective targets for various genetic alterations in breast cancer
Solution Approach 1:
The invention segments the cancer therapy approach by identifying specific genetic alterations (spliceosome mutations) and their corresponding molecular consequences (cryptic splice site usage, MASAs) to create targeted therapeutic strategies for different cancer subtypes
Solution Approach 2:
The invention performs preliminary identification and characterization of MASAs and their association with spliceosome mutations before clinical application, using engineered cell lines and computational methods to prepare targeted antigens for future therapeutic use
2Ease of manufacture
If research focuses on common cancer mutations, then therapeutic targets can be identified, but most cancer mutations occur in only a few percent of cases complicating prioritization
Solution Approach 1:
The invention changes the research parameter from focusing on mutation frequency to focusing on the functional consequences of mutations (cryptic splice site activation, MASA production), allowing identification of therapeutic targets across rare and common mutations alike
3Measurement precision
If isogenic cell lines are engineered to express mutated spliceosome proteins, then mis-splicing-associated surface antigens can be identified, but the process requires complex genetic engineering
Solution Approach 1:
The invention uses engineered isogenic cell lines as intermediaries to bridge the gap between spliceosome mutations and MASA identification, allowing systematic study of mutation-antigen relationships in a controlled setting
Solution Approach 2:
The engineered cell lines serve multiple functions: they express mutated spliceosome proteins, produce cryptic splice variants, display MASAs on their surface, and provide a platform for antibody screening and therapeutic development
Data Source
AI summary
The present disclosure relates to compositions and methods for treating cancers. In particular, the present disclosure provides materials and methods for identifying mis-splicing-associated surface antigens (MASAs) generated by altered spliceosome proteins, as well as materials and methods for targeting cancerous tumors expressing MASAs.