AHL analogs sensitizing cancer cells to TRAIL via transient UPR activation

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Solution Overview

Problem

Cancer cells often develop resistance to TRAIL-induced apoptosis, limiting the efficacy of TRAIL treatment, and existing methods to overcome resistance, such as UPR activators, induce constitutive and sustained activation, which can be harmful.

Innovation Solution

The use of bacterial acylhomoserine lactone (AHL) analogs, specifically compounds like C12, which inhibit NF-κB signaling and modulate sphingolipid metabolism, synergizes with TRAIL to induce apoptosis in cancer cells while sparing normal cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If UPR activators such as tunicamycin, thapsigargin and α-TEA are used to sensitize cancer cells to TRAIL-induced apoptosis, then cancer cell sensitivity to TRAIL is improved, but constitutive and sustained activation of the UPR occurs which can be harmful

Engineering Contradiction:

Improvecancer cell sensitivity to TRAILVSAvoidconstitutive and sustained activation of UPR

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent uses bacterial metabolites (AHLs) that transiently activate the UPR, changing the temporal parameter of UPR activation from sustained (UPR activators) to transient (bacterial metabolites). This transient activation is sufficient to sensitize cancer cells to TRAIL while avoiding the harmful constitutive activation caused by traditional UPR activators

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs bacterial metabolites as transient, short-living UPR activators that perform their function and are then degraded. This contrasts with traditional UPR activators that cause sustained activation. The transient nature of bacterial metabolite-induced UPR activation allows for effective cancer cell sensitization without the harmful long-term effects of constitutive UPR activation

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Object-affected harmful factors

If TRAIL is used to induce apoptosis in cancer cells, then selective toxicity to human tumor xenografts is achieved, but cancer cells develop resistance limiting treatment efficacy

Engineering Contradiction:

Improveselective toxicity to cancer cellsVSAvoidtreatment efficacy

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent applies preliminary action by using bacterial metabolites to transiently activate the UPR and sensitize cancer cells to TRAIL before TRAIL treatment. This preliminary sensitization step overcomes cancer cell resistance mechanisms, allowing TRAIL to effectively induce apoptosis in otherwise resistant cells while maintaining selective toxicity

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent merges the effects of bacterial metabolite-induced UPR activation with TRAIL treatment to create a synergistic anti-cancer therapy. The combination of transient UPR activation and TRAIL induces enhanced apoptosis in cancer cells compared to either agent alone, overcoming resistance while maintaining selectivity

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentEP2976076B1Trail enhancers for the selective killing of cancer cells

Publication Date: 2020.03.04 THE SCRIPPS RES INST

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AI summary

The invention is directed to methods of inducing apoptosis, arresting cell cycle, or inhibiting cellular proliferation, or any combination thereof, in a tumor cell, by administration of an effective amount of an N-acyl homoserine lactone analog (AHL), optionally in conjunction with a tumor modulating agent such tumor necrosis factor (TNF) related apoptosis inducing ligand (TRAIL) to the patient. Novel bioactive analogs of an N-acyl homoserine lactone are also provided.