EMT Cell Models for Targeting Resistant Tumor Cells
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Solution Overview
Problem
Current cancer therapies face challenges in selectively targeting and effectively inhibiting tumor cells, especially after epithelial-to-mesenchymal transition (EMT), leading to resistance and cross-resistance issues, and existing agents have narrow therapeutic indexes and limited efficacy against metastatic cells.
Innovation Solution
Development of EMT cell models using the epithelial tumor cell line H358, engineered to inducibly express proteins that stimulate EMT, allowing for the identification of agents that inhibit EMT, stimulate mesenchymal-to-epithelial transition (MET), or inhibit mesenchymal-like cell growth, in combination with EGFR or IGF-1R kinase inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current chemotherapies are used to treat cancer cells, then they can kill cancer cells to some extent, but they develop resistance and cross-resistance quickly, leading to narrow therapeutic indexes and limited efficacy
Solution Approach 1:
The patent applies preliminary action by inducing EMT in tumor cells before treating them with chemotherapeutic agents. The method pre-transforms epithelial tumor cells into mesenchymal-like cells that are more resistant to conventional chemotherapy, thereby modeling the resistance development process and enabling identification of agents that can overcome this resistance. This preliminary transformation allows researchers to screen for compounds that maintain efficacy against resistant cell states.
2Quantity of substance
If chemotherapeutic agents are used to inhibit tumor cell growth, then they can reduce tumor burden, but they lack selectivity and have narrow therapeutic indexes relative to toxicity towards non-malignant cells
Solution Approach 1:
The patent applies local quality by creating distinct cell states with different properties. By inducing EMT, the tumor cells acquire mesenchymal characteristics (increased motility, resistance to apoptosis) that distinguish them from both normal epithelial cells and untreated tumor cells. This local transformation allows for more selective targeting strategies, as agents can be designed to specifically recognize and act upon mesenchymal markers or pathways without affecting normal non-malignant cells that retain their differentiated state.
3Adaptability or versatility
If tumor cells undergo EMT to become more invasive and metastatic, then they gain ability to invade local tissues and metastasize, but they become less responsive to conventional chemotherapies and kinase inhibitors
Solution Approach 1:
The patent applies dynamics by creating a dynamic cell model that can transition between epithelial and mesenchymal states. The induced EMT system allows tumor cells to adapt their phenotype in response to therapeutic pressure, mimicking the clinical progression from sensitive to resistant states. This dynamic transformation enables researchers to study temporal changes in drug responsiveness and identify agents that can effectively target cells at different stages of the EMT process, thereby maintaining therapeutic efficacy against adaptive, invasive tumor populations.
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AI summary
The present invention provides tumor cell preparations for use as models of the EMT process for use in the identification of anti-cancer agents, wherein said tumor cell preparations comprise cells of the epithelial tumor cell line H358, which are stimulated by receptor ligands to induce EMT, or which have been engineered to inducibly express a protein that stimulates EMT. The present invention also provides methods of identifying potential anti-cancer agents by using such tumor cell preparations to identify agents that inhibit EMT, stimulate MET, or inhibit the growth of mesenchymal-like cells. Such agents should be particularly useful when used in conjunction with other anti-cancer drugs such as EGFR and IGF-IR kinase inhibitors, which appear to be less effective at inhibiting tumor cells that have undergone an EMT.