PARP Plus dU Analog Therapy for DNA Damage in p53-Deficient Cancers
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Solution Overview
Problem
Current therapeutic options for p53-deficient cancers, such as triple-negative breast cancer and gastrointestinal tract cancers, are inadequate as they often relapse and progress to metastatic disease, necessitating a need for better treatment strategies.
Innovation Solution
A combination therapy using deoxyuridine (dU) analogs, such as TAS-102, and poly (ADP-ribose) polymerase inhibitors (PARPi), like olaparib or talazoparib, is administered to selectively induce DNA damage and cell death in p53-deficient cancer cells while sparing normal cells with wild-type p53 through the p53-p21 axis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemotherapy regimens are used to treat p53-deficient cancers, then initial response is high, but cancers relapse and progress to metastatic disease
Solution Approach 1:
The patent employs deoxyuridine analogs to preliminarily induce DNA damage and activate BER pathways in p53-deficient cancer cells before administering PARP inhibitors. This preliminary action creates a vulnerable state in cancer cells by upregulating BER activity, which then makes them more susceptible to PARP inhibitor-induced DNA damage, preventing relapse and metastasis
Solution Approach 2:
The patent uses the BER pathway as an intermediary mechanism between the deoxyuridine analogs and PARP inhibitors. The deoxyuridine analogs activate BER, which then serves as the mediator that amplifies DNA damage when PARP inhibitors are administered, creating a synergistic effect that eliminates residual cancer cells and prevents disease progression
2Object-affected harmful factors
If deoxyuridine analogs are administered alone, then DNA damage is induced in cancer cells, but normal cells can escape using the p53-p21 axis and cell cycle arrest
Solution Approach 1:
The patent exploits the local quality difference in p53 status between cancer cells (p53-deficient) and normal cells (p53-wild type). Deoxyuridine analogs selectively induce DNA damage in p53-deficient cancer cells, while normal cells with functional p53-p21 axis can arrest the cell cycle and repair DNA, creating selective toxicity against cancer cells
Solution Approach 2:
The patent changes the parameter of DNA repair pathway activity by administering deoxyuridine analogs that specifically upregulate BER pathways in p53-deficient cancer cells. This parameter change creates a differential response where cancer cells become more vulnerable to DNA damage while normal cells maintain their protective p53-mediated DNA repair capabilities
3Object-affected harmful factors
If PARP inhibitors are used to enhance DNA damage in p53-deficient cells, then cancer cell death is increased, but combination therapy complexity increases
Solution Approach 1:
The patent merges two distinct mechanisms (deoxyuridine analog-induced DNA damage and PARP inhibitor-enhanced DNA damage) into a unified combination therapy. This merging creates a synergistic effect where the two agents work together to amplify DNA damage in p53-deficient cancer cells, overcoming the limitations of monotherapy while managing treatment complexity through coordinated administration
Data Source
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AI summary
Provided are methods and formulations for the treatment of p53-deficient cancers using a combinational drug strategy which enhances DNA damage in p53 deficient cells while not allowing cells to escape cell death by activation of p53-p21 signaling. Wild-type p53 carriers, on the other hand, respond with activation of p53-p21 signaling and cell-cycle arrest, thereby escaping cell death. The methods involve administering to an individual in need of treatment a combination of one or more poly (ADP ribose) polymerase inhibitors (PARPi) and one or more deoxyuridine analogs. Pharmaceutical formulations comprising PARPi and dU analogs are also provided.