LIG1 and FANCM Blocking Agents for Synthetic Lethality in Cancer
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Solution Overview
Problem
There is a long-felt need for an effective and safe cancer therapeutic that can selectively target impaired or deregulated DNA repair pathways in cancer cells, particularly those with impaired homologous recombination (HR) repair pathways, to induce cell death or cell cycle arrest.
Innovation Solution
The use of DNA ligase 1 (LIG1) and Fanconi Anemia Group M protein (FANCM) blocking agents that specifically inhibit the function of LIG1 and FANCM in cancer cells with impaired HR repair pathways, thereby inducing DNA damage and reducing cell growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer treatments are used, then some cancer cells are killed, but cancer cells with impaired HR repair pathways develop resistance
Solution Approach 1:
The patent converts the previously harmful trait of impaired HR repair pathways (which caused treatment resistance) into a beneficial vulnerability. By using LIG1 and FANCM blocking agents, the therapy exploits the cancer cells' defective DNA repair mechanisms to induce synthetic lethality, where the cells die from accumulated DNA damage rather than resist treatment
Solution Approach 2:
The patent changes the therapeutic parameter from general cytotoxicity to pathway-specific inhibition. By targeting LIG1 and FANCM proteins in cells with impaired HR pathways, the treatment shifts from non-specific cell killing to precision inhibition of DNA repair capacity, thereby overcoming resistance while maintaining effectiveness
2Reliability
If DNA repair pathways are inhibited to kill cancer cells, then cell death is induced, but normal cells with functional DNA repair are also affected
Solution Approach 1:
The patent applies local quality by making the therapeutic effect specific to cancer cells with impaired HR pathways. The LIG1 and FANCM blocking agents exert their cytotoxic effect preferentially in cells that already have defective HR repair, while normal cells with functional DNA repair pathways can compensate and avoid damage
Solution Approach 2:
Instead of protecting normal cells from DNA damage, the patent inverts the approach by selectively damaging cancer cells through their vulnerability. The impaired HR pathway becomes the target rather than the protection target, allowing therapeutic action against cancer while sparing normal tissue
3Productivity
If LIG1 and FANCM are blocked in cells with impaired HR pathways, then DNA damage accumulates and cell growth stops, but the mechanism requires specific pathway impairment
Solution Approach 1:
The patent applies self-service by allowing the cancer cells' own defective HR pathways to serve the therapeutic mechanism. The impaired pathway automatically creates synthetic lethality when LIG1 and FANCM are inhibited, without requiring external modification or activation of the defect
Data Source
AI summary
The disclosure provides compositions and methods for the selective targeting of components of a first or a second DNA repair pathway in cancer cells having an impaired, defective or deregulated first DNA repair pathway. In some embodiments of the disclosure, the disclosure provides a composition comprising a DNA ligase 1 (LIG1) blocking agent, wherein in a target cell comprising an impaired, defective or deregulated homologous recombination (HR) repair pathway, the blocking agent reduces or inhibits a function of LIG1. In some embodiments of the disclosure, the disclosure provides composition comprising a Fanconi Anemia Group M protein (FANCM) blocking agent, wherein in a target cell comprising an impaired, defective or deregulated homologous recombination (HR) repair pathway, the blocking agent reduces or inhibits a function of FANCM. The disclosure further provides methods for using compositions of the disclosure for the treatment of cancer.