Androgen Receptor Splice Variants as Prognostic Biomarkers

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Solution Overview

Problem

Current therapies for prostate cancer, particularly androgen refractory prostate cancer, are ineffective due to the continued expression of androgen receptor (AR) signaling pathways despite androgen ablation, with existing anti-androgen drugs unable to inhibit novel AR splice variants that lack the ligand binding domain, leading to androgen-independent growth.

Innovation Solution

Identification and characterization of novel AR splice variants (AR3, AR4, AR4b, AR5, and AR8) that are constitutively active and lack the ligand binding domain, along with the development of methodologies to modulate these variants using antisense technology, RNAi, ribozymes, and antibodies to inhibit their activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional androgen ablation therapy is used to treat prostate cancer, then initial tumor remission is achieved through apoptosis of androgen-sensitive cells, but the disease inevitably progresses to androgen-independent recurrence that is resistant to further hormone therapy

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidduration of hormone therapy response

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent segments the androgen receptor into different splice variants (AR1-AR8) with distinct functional domains. By identifying and targeting specific variants like AR3, AR4, AR5, and AR8 that lack the ligand binding domain, the therapy can specifically inhibit androgen-independent growth pathways while preserving normal androgen-dependent functions.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent extracts and isolates specific AR splice variants from the complex AR protein family. By removing the ligand binding domain through alternative splicing, certain AR variants become constitutively active and drive androgen-independent growth. The invention targets these extracted variants specifically with novel therapies.

Inventive Principle:

Principle #2Taking out (Extraction)

2Reliability

If existing anti-androgen drugs are used to inhibit AR signaling, then androgen-dependent prostate cancer growth is suppressed, but they cannot inhibit novel AR splice variants that lack the ligand binding domain

Engineering Contradiction:

Improveinhibition of AR signalingVSAvoidability to inhibit AR variants

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by targeting specific regions or domains of the AR protein family. Instead of treating all AR variants uniformly, the invention identifies specific splice variants (AR3, AR4, AR5, AR8) that lack the ligand binding domain and are constitutively active, and develops therapies specifically directed at these local variants with distinct properties.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Instead of trying to block androgen binding to inhibit AR activity (the conventional approach), the invention inverts the strategy by targeting AR splice variants that inherently lack the ligand binding domain and are constitutively active. This approach shifts from preventing androgen-dependent activation to directly inhibiting androgen-independent growth pathways.

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If AR mutations or amplification are present in prostate cancer, then androgen-independent growth can occur, but such mutations are present in only less than 10% of cases

Engineering Contradiction:

Improvemechanism of androgen independenceVSAvoidfrequency of AR mutations

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent changes the parameter of AR expression by identifying alternative splice variants that arise from different transcriptional processing of the AR gene. Instead of relying on mutations or amplification (which occur in <10% of cases), the invention focuses on splice variants like AR3, AR4, AR5, and AR8 that are produced through alternative splicing and are constitutively active, providing a more widespread mechanism for androgen independence.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS8133724B2Human androgen receptor alternative splice variants as biomarkers and therapeutic targets

Publication Date: 2012.03.13 UNIV OF MARYLAND

AI summary

The present invention relates to novel androgen receptor splice variants (AR3, AR4, AR4b, AR5 and AR8) and variants and fragments thereof which have a role in the progression of androgen independent prostate cancer. The invention further relates to compositions and methods which can be used to identify and treat prostate cancer based on these novel androgen receptor splice variants, as well as methods for screening agents which modulate the activity and/or expression of the androgen receptor splice variants. Vectors, host cells and recombinant methods for producing the same and transgenic animals are also provided.