BH3 Profiling for Cancer Cell Chemosensitivity Prediction

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Solution Overview

Problem

Current methods lack an effective way to predict cancer cell sensitivity to therapeutic agents by measuring mitochondrial outer membrane permeabilization induced by BH3 domain peptides, which is crucial for determining chemosensitivity and apoptosis.

Innovation Solution

The method involves contacting a test cell population with BH3 domain peptides, measuring mitochondrial outer membrane permeabilization, and comparing the results to a control population to assess sensitivity, using techniques such as potentiometric or radiometric dyes and antibodies to detect changes like cytochrome c release.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If current methods are used to assess cancer cell sensitivity, then general chemotherapy approaches are applied, but they lack precision in predicting individual cell response and do not effectively measure mitochondrial outer membrane permeabilization

Engineering Contradiction:

Improveprediction precision of cancer cell sensitivityVSAvoidmethod complexity

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The method segments the assessment of cancer cell sensitivity by using a panel of individual BH3 domain peptides (BID, BIM, BAD, BIK, NOXA, PUMA) to profile specific apoptotic pathways. Each peptide targets specific BCL-2 family members, allowing precise measurement of mitochondrial outer membrane permeabilization through cytochrome c release detection, thereby achieving high prediction precision without excessive overall complexity

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention introduces BH3 domain peptides as intermediary molecules that mediate between the therapeutic agent and the mitochondrial membrane. These peptides bind to anti-apoptotic BCL-2 family members and induce conformational changes that lead to mitochondrial outer membrane permeabilization, serving as measurable intermediaries to predict cell sensitivity to chemotherapy

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If BH3 domain peptides are used to measure mitochondrial outer membrane permeabilization, then accurate chemosensitivity prediction is achieved, but the measurement and comparison procedures become more complex

Engineering Contradiction:

Improvechemosensitivity prediction reliabilityVSAvoidoperation simplicity

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The method performs preliminary actions by first contacting cells with a panel of BH3 domain peptides to establish a baseline BH3 profile before exposing cells to the therapeutic agent. This preliminary profiling of mitochondrial outer membrane permeabilization responses to individual peptides creates a reference framework that simplifies subsequent sensitivity assessment and enables reliable prediction without requiring complex real-time measurements during therapy

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention implements feedback by comparing the BH3 profile of test cells (exposed to therapeutic agent) with control cells (unexposed). The measurement of cytochrome c release and mitochondrial outer membrane permeabilization provides feedback signals that indicate whether the cell population has become sensitized to the therapeutic agent, allowing for reliable chemosensitivity prediction through systematic comparison

Inventive Principle:

Principle #23Feedback

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 approach allows for the prediction of cancer cell sensitivity to therapeutic agents by identifying increased mitochondrial membrane permeabilization, indicating apoptosis and thus chemosensitivity, with statistically significant results.

Implementation Method 1

measuring the amount of BH3 domain peptide induced mitochondrial outer membrane permeabilization in the test cell population

Methodology Applied

Scientific EffectMitochondrial outer membrane permeabilization:

Implementation Method 2

measuring the amount of BH3 domain peptide induced mitochondrial outer membrane permeabilization in the test cell population; using techniques such as potentiometric or radiometric dyes

Methodology Applied

Scientific EffectPotentiometric detection:

Implementation Method 3

using techniques such as potentiometric or radiometric dyes and antibodies to detect changes like cytochrome c release

Methodology Applied

Scientific EffectRadiometric detection:

Implementation Method 4

using techniques such as potentiometric or radiometric dyes and antibodies to detect changes like cytochrome c release

Methodology Applied

Scientific EffectAntibody-antigen binding:

Data Source

PatentUS11867687B2Methods of BH3 profiling

Publication Date: 2024.01.09 DANA FARBER CANCER INSTITUTE INC

AI summary

The present invention provides methods of determining cell sensitivity to a therapeutic agent.