NXTAR Oligonucleotides Suppressing AR Variants in Resistant Prostate Cancer

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Solution Overview

Problem

Current treatments for prostate cancer, particularly castration-resistant prostate cancer (CRPC), often develop resistance to androgen receptor (AR) antagonists like enzalutamide, and there is a need for alternative strategies to suppress AR expression and its variants, such as AR-V7, which are resistant to existing therapies.

Innovation Solution

The use of NXTAR-derived oligonucleotides, which are designed to target and suppress AR expression by binding to specific sequences, thereby inhibiting AR and AR-V7 mRNA expression and cancer cell proliferation, even in resistant cases, using formulations like nanoparticles for delivery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If AR antagonists like enzalutamide are used to treat prostate cancer, then AR activity is inhibited, but cancer cells develop resistance over time

Engineering Contradiction:

Improvetreatment efficacyVSAvoidduration of response

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

Instead of using antagonists that block AR function, the invention uses oligonucleotides that bind to AR mRNA to prevent its translation. This inverse approach targets the mRNA level rather than the protein level, overcoming resistance that develops to traditional AR-targeted therapies

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention extracts and targets specific mRNA sequences (AR and AR-V7) using complementary oligonucleotides. By designing oligos that specifically bind to and suppress these mRNA transcripts, the treatment directly removes the problematic genetic material without affecting the protein directly, thereby avoiding resistance mechanisms

Inventive Principle:

Principle #2Taking out (Extraction)

2Productivity

If traditional AR-targeted therapies are used, then initial response is achieved, but resistance develops to AR antagonists

Engineering Contradiction:

Improveinitial treatment responseVSAvoidresistance development

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The oligonucleotides are designed to preemptively target and suppress AR mRNA before it can be translated into protein. This preliminary action at the mRNA level prevents the formation of AR protein, including resistant variants like AR-V7, before resistance can develop

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention introduces oligonucleotide intermediaries that bind to AR mRNA as a mediator between the treatment and the target. These oligos serve as intermediaries that specifically recognize and suppress AR mRNA sequences, providing a new mechanism of action that bypasses resistance to direct AR antagonists

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS12194057B2NXTAR-derived oligonucleotides and uses thereof

Publication Date: 2025.01.14 WASHINGTON UNIV IN SAINT LOUIS

AI summary

Among the various aspects of the present disclosure is the provision of a NXTAR-derived oligonucleotides and uses thereof. An aspect of the present disclosure provides for a method of (i) suppressing androgen receptor (AR) expression, (ii) suppressing androgen receptor splice variants (including AR-V7) expression, (iii) treating cancer (e.g., prostate, breast, testis, ovarian, endometrial and skin) (iv) treating skin related diseases, such as androgenetic alopecia and acne vulgaris in a subject comprising administering to the subject a NXTAR-derived oligonucleotide (oligo) (NXTAR is a lncRNA also known as LOC105373241).