Targeting 3betaHSD1 N367T Mutation in CRPC

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Solution Overview

Problem

Castration-resistant prostate cancer (CRPC) progresses due to increased intratumoral dihydrotestosterone (DHT) synthesis, which is not effectively targeted by current therapies, as existing treatments do not address the gain-of-function mutation in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) that enhances DHT production, leading to resistance against androgen deprivation therapy.

Innovation Solution

Identifying and targeting the gain-of-function mutation in 3βHSD1, specifically the N367T variant, which increases DHT synthesis by rendering the enzyme resistant to ubiquitination and degradation, thereby inhibiting its activity to impede CRPC growth.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If androgen deprivation therapy is used to treat prostate cancer, then tumor growth is initially suppressed, but the cancer eventually progresses to castration-resistant prostate cancer (CRPC) with increased DHT synthesis

Engineering Contradiction:

Improveefficacy of androgen deprivation therapyVSAvoidduration of therapy effectiveness

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent identifies and targets the gain-of-function mutation in 3βHSD1 (N367T) as a preliminary action to prevent CRPC development. By inhibiting this mutated enzyme before resistance fully develops, the therapy aims to block the metabolic pathway that produces intratumoral DHT, thereby preventing the transition from treatment-sensitive to treatment-resistant disease state

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent focuses on changing the enzymatic activity parameter of 3βHSD1 through targeted inhibition. The N367T mutation increases enzyme activity and stability, and the invention applies inhibitors to reverse this parameter change, restoring normal DHT synthesis levels and maintaining therapy effectiveness beyond the typical resistance timeline

Inventive Principle:

Principle #35Parameter changes

2Productivity

If 3βHSD1 activity is increased due to the N367T mutation, then DHT synthesis is enhanced and CRPC progression is driven, but current therapies cannot effectively target this mutated enzyme

Engineering Contradiction:

ImproveDHT synthesis rateVSAvoidtargetability by existing therapies

Core Design Contradiction:

ProductivityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by designing inhibitors that specifically target the N367T mutated form of 3βHSD1 rather than attempting to inhibit all 3βHSD1 activity systemically. The inhibition is localized to the mutated enzyme variant that is overexpressed in CRPC cells, preserving normal physiological functions while blocking the pathological DHT synthesis pathway

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent introduces small molecule inhibitors as intermediary agents that mediate between the mutated 3βHSD1 enzyme and the androgen receptor pathway. These inhibitors bind to the mutated enzyme and prevent substrate conversion, acting as a chemical intermediary that blocks the aberrant metabolic pathway without directly interacting with the androgen receptor or other therapy targets

Inventive Principle:

Principle #24Intermediary (Mediator)

3Stability of the object's composition

If the N367T mutation renders 3βHSD1 resistant to ubiquitination and degradation, then enzyme stability and DHT production increase, but this creates resistance to standard treatments

Engineering Contradiction:

Improveenzyme stabilityVSAvoidtreatment response

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent converts the harmful effect of increased enzyme stability into a beneficial therapeutic target. The N367T mutation's conferral of resistance to ubiquitination and degradation, which normally causes treatment resistance, is instead exploited as a specific target for novel inhibitors. By designing compounds that specifically recognize and inhibit the stabilized mutated enzyme, the harmful stability is converted into a reliable target for maintaining treatment response

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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

Silencing or inhibiting the 3βHSD1 N367T variant significantly reduces DHT production, inhibiting CRPC growth and progression, offering a potential therapeutic strategy to overcome resistance to standard treatments.

Implementation Method 1

3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in the conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 2

The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation

Methodology Applied

Scientific EffectUbiquitination resistance:

Data Source

PatentUS10533228B23.beta-hydroxysteroid dehydrogenase in steroid dependent disease

Publication Date: 2020.01.14 THE CLEVELAND CLINIC FOUND

AI summary

Methods and kits for characterizing a subject having a steroid-dependent disease such as prostate cancer are described. A method of treating a steroid-dependent disease in a subject by obtaining a biological sample from the subject, determining if the HSD3B1(1245C) gene or 3βHSD1(367T) protein is expressed in the biological sample, and providing treatment other than or in addition to steroid ablation to the subject if the HSD3B1(1245C) gene or 3βHSD1(367T) protein is expressed is also described.