OKI-179 HDAC Inhibitor Combination Therapy for Cancer
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Solution Overview
Problem
Current treatments for cancers with RAS pathway mutations, such as colorectal and lung cancers, have limited efficacy as single agents, highlighting the need for rational targeted combinations to improve patient outcomes.
Innovation Solution
The use of OKI-179, a potent Class I-selective HDAC inhibitor, in combination with MEK inhibitor binimetinib and BRAF inhibitor encorafenib, administered according to specific dosing schedules, to treat cancers with NRAS or BRAF mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If RAS-pathway targeted drugs are used as single agents, then treatment is simple, but therapeutic activity remains modest
Solution Approach 1:
The patent combines RAS-pathway targeted drugs with HDAC inhibitors to create a combination therapy that achieves synergistic effects. This merging of two different drug classes addresses the modest activity of single agents by creating a multi-targeted approach that simultaneously inhibits RAS signaling and enhances DNA damage response, thereby improving therapeutic outcomes while maintaining treatment feasibility
2Reliability
If HDAC inhibitors are used in combination therapies, then tumor regression is enhanced, but safety issues and dosing inconvenience increase
Solution Approach 1:
The patent implements a specific dosing schedule where OKI-179 is administered on days 1-5 of a 7-day cycle, creating periodic treatment intervals. This periodic action allows sufficient time for drug clearance and recovery between doses, reducing cumulative toxicity and safety issues while maintaining effective tumor regression through sustained inhibition of DNA repair pathways in cancer cells
3Reliability
If HDAC inhibitors are used in combination therapies, then synthetic lethality is achieved, but dosing inconvenience increases
Solution Approach 1:
The patent segments the treatment cycle into distinct phases: OKI-179 is given on days 1-5, followed by a 2-day break, while binimetinib is administered continuously. This segmentation allows each drug to be optimized for its specific pharmacokinetic profile and mechanism of action, achieving synthetic lethality through coordinated timing while making the dosing schedule more manageable and less inconvenient than continuous daily administration of all agents
Data Source
AI summary
A method of treating cancer in a subject in need thereof, wherein the method comprises administration of therapeutically effective amounts of OKI-179 and binimetinib or a pharmaceutically acceptable salt thereof, or administration of therapeutically effective amounts of OKI-179, binimetinib or a pharmaceutically acceptable salt thereof, and encorafenib or a pharmaceutically acceptable salt thereof according to the dosing schedules described herein.