RUNX3–BRD2 Complex Maintenance Using CDK4 or mTOR Inhibitors
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Solution Overview
Problem
Current strategies to treat K-Ras mutant lung cancer by activating tumor suppressor genes like p53 or Rb have been unsuccessful, and there are no effective treatments for K-Ras mutant lung adenocarcinoma, as the cancer rapidly progresses to a malignant state even with restored gene function.
Innovation Solution
A pharmaceutical composition combining a modified Runx3 protein with a CDK4 inhibitor or an mTOR inhibitor is used to maintain the Runx3-BRD2 complex, enhancing cancer apoptotic effects in Runx3 deficient cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tumor suppressor gene function is restored (p53 or Rb), then gene function is improved, but therapeutic effect on already-onset cancer does not appear because cancer rapidly develops into malignant state
Solution Approach 1:
The patent introduces Runx3 protein in advance to prevent cancer development at early stages before malignancy occurs. By restoring Runx3 function proactively in pre-cancerous or early-stage conditions, the treatment aims to stop cancer progression before it becomes aggressive and treatment-resistant, addressing the time loss issue by acting early rather than waiting for established cancer
Solution Approach 2:
The patent combines Runx3 protein administration with CDK4 inhibitor or mTOR inhibitor treatment to modify the biological parameters of cancer cell behavior. This combination therapy changes the cellular environment and signaling pathways to enhance the effectiveness of tumor suppressor restoration, overcoming the limitation of simple gene restoration by creating multiple concurrent therapeutic effects
2Reliability
If K-Ras function is directly inhibited, then oncogene function is suppressed, but serious damage to normal cells occurs
Solution Approach 1:
Instead of directly inhibiting the oncogenic K-Ras pathway (which harms normal cells), the patent inverts the strategy by activating the inhibited tumor suppressor Runx3. This reverse approach restores the body's natural defense mechanisms against cancer, allowing normal cells to function properly while selectively targeting cancer cells through the reactivated tumor suppressor pathway
3Reliability
If Runx3 protein is administered alone, then tumor suppressor function is restored, but cancer apoptotic effect is insufficient
Solution Approach 1:
The patent merges Runx3 protein administration with CDK4 inhibitor or mTOR inhibitor treatment to create a synergistic combination therapy. This combination integrates multiple therapeutic mechanisms: Runx3 restoration of tumor suppressor function plus inhibition of cell cycle progression and mTOR signaling, thereby enhancing the overall cancer apoptotic effect beyond what either treatment could achieve alone
Data Source
AI summary
The present invention relates to a pharmaceutical composition for prevention or treatment of cancer, comprising a Runx3 (Runt-related transcription factor 3) protein, a polynucleotide encoding thereof, a vector carrying the polynucleotide or a virus or cell transformed with the vector; and a CDK4 inhibitor or an mTOR inhibitor as an active ingredient. It was confirmed that the binding of Runx3 and BRD2 was maintained for up to 8 hours when the CDK4 inhibitor (PD0332991) was present at the concentration of 11 nM known to be non-toxic to normal cells. It was also confirmed that the binding of Runx3 and BRD2 was maintained for up to 8 hours when the mTOR inhibitor (rapamycin) was present at the concentration of 100 nM known to be non-cytotoxic to normal cells. In addition, it was confirmed that the cancer apoptotic effect was significantly increased when the CDK4 inhibitor or mTOR inhibitor was administered simultaneously with Runx3 than when Runx3 was administered alone to Runx3 deficient cancer cells. Therefore, the CDK4 inhibitor or mTOR inhibitor can be effectively used for preventing or treating various cancers by administering the same in combination with Runx3.