Sequential Calcium Disruption and DR5 Agonism for Senescent Cell Killing
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Solution Overview
Problem
The lack of universal senolytic agents that can selectively target senescent cancer cells in a context-independent manner with an acceptable toxicity profile poses a challenge in cancer therapy, as senescent cells can be harmful due to chronic inflammation and promote tumor growth.
Innovation Solution
A combination therapy using a calcium homeostasis disruptor, such as salinomycin, with a selective Death Receptor 5 (DR5) agonist, like an antibody, is administered sequentially to induce senescence and enhance apoptosis in senescent cells, leveraging the synergistic effect to eliminate these cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If senescence-inducing therapy is used to arrest tumor cell proliferation, then tumor growth is suppressed, but prolonged presence of senescent cells causes chronic inflammation and promotes tumor migration and metastasis
Solution Approach 1:
The patent extracts and eliminates the harmful senescent cells from the tumor microenvironment using a two-step approach: first inducing senescence with pro-senescence therapy, then selectively removing these senescent cells using senolytic agents that target specific pathways (such as BCL-2 inhibition or DR5 agonism) upregulated in senescent cells, thereby removing the source of chronic inflammation and metastatic promotion while preserving the initial growth suppression benefit
Solution Approach 2:
The patent converts the harmful SASP secreted by senescent cells into a beneficial therapeutic target by designing senolytic agents that specifically recognize and bind to components of the SASP pathway (such as DR5 receptors or anti-apoptotic proteins) that are overexpressed in senescent cells, thereby transforming the harmful inflammatory signal into a selective vulnerability that can be exploited for therapeutic elimination of senescent cells
2Reliability
If universal senolytic agents are developed to selectively target senescent cancer cells, then senescent cell elimination is achieved, but context-independent selectivity and acceptable toxicity profile are difficult to obtain
Solution Approach 1:
The patent develops senolytic agents with universal mechanisms that target fundamental pathways common to senescent cells across different cancer types and contexts, such as the BCL-2 family of anti-apoptotic proteins or the DR5 death receptor pathway, allowing a single agent to effectively eliminate senescent cells regardless of the specific cancer context or senescence-inducing therapy used, thereby achieving both selectivity and versatility
Solution Approach 2:
The patent exploits parameter changes in senescent cells, specifically the upregulation of certain pathways (such as BCL-2 expression or DR5 sensitivity) that occur universally in senescent states regardless of the inducing stimulus, and designs agents that specifically target these altered parameters, thereby achieving context-independent selectivity through detection and exploitation of the senescent state's characteristic molecular profile
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This combination effectively eliminates senescent cells, reducing tumor growth and metastasis by inducing a PANoptosis phenotype, while maintaining a favorable toxicity profile.
Implementation Method 1
the disruptor is the ionophore antibiotic salinomycin
Data Source
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AI summary
The invention relates to a calcium homeostasis disruptor in combination with a selective Death Receptor 5 (DR5) agonist for use in a method of treating a patient suffering from a tumor. The invention further relates to a pharmaceutical composition, comprising a calcium homeostasis disruptor in combination with a selective Death Receptor 5 (DR5) agonist and, optionally, an inducer of senescence. The invention further relates to methods of treating a patient having a tumor, and to a calcium homeostasis disruptor in combination with a selective DR5 agonist, for use in a method of selectively killing senescent cells, including senescent cancer cells.