Splice-Switching Oligonucleotides Target AR and EGFR in Prostate Cancer
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Solution Overview
Problem
Prostate cancer disparities exist among African American men, with higher incidence and mortality rates compared to white men, largely due to differences in gene expression and up-regulation of oncogenic signaling pathways like androgen receptor (AR) and epidermal growth factor receptor (EGFR). Current therapeutic strategies are inadequate in addressing these disparities and limiting aberrant constitutively active AR isoforms.
Innovation Solution
The use of splice-switching oligonucleotides (SSOs) that target specific regions of the AR and EGFR genes, such as the 5' splice site of Exon 1 or CE3 of AR, or exons 16 and 18 of EGFR, to modulate splicing and reduce the expression of these receptors in cancer cells. These SSOs can produce inhibitory isoforms or dominant-negative variants, thereby limiting the progression of prostate cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapeutic strategies are used, then general cancer treatment is provided, but they are inadequate in addressing prostate cancer disparities and limiting aberrant constitutively active AR isoforms
Solution Approach 1:
The patent applies local quality by designing oligonucleotides with specific sequences that target particular splice sites (5' splice site of Exon 1 or CE3 of AR, exons 16 and 18 of EGFR) rather than using general therapeutic approaches. This localized targeting enables selective modulation of specific isoforms (AR-V7, AR-45, EGFRvIII) while preserving normal receptor function, thereby addressing the inadequacy of conventional therapies in targeting specific molecular mechanisms underlying prostate cancer disparities
Solution Approach 2:
The patent segments the therapeutic approach by dividing the oligonucleotide into distinct functional regions: a 5' untranslated region (5' UTR) for stability and a coding region for splice site recognition. This segmentation allows independent optimization of each region's function, enabling the oligonucleotide to simultaneously achieve stable expression and specific splice site binding, thereby improving treatment effectiveness while maintaining adaptability to specific molecular targets
2Reliability
If splice-switching oligonucleotides are used to modulate splicing, then production of inhibitory AR and EGFR isoforms is driven, but the complexity of the therapeutic approach increases
Solution Approach 1:
The patent uses the oligonucleotide as an intermediary molecule that mediates between the cellular splicing machinery and the target pre-mRNA. The oligonucleotide contains a coding region that hybridizes to the 5' splice site and a 5' UTR that recruits splicing factors, acting as a bridge to redirect splicing toward inhibitory isoforms. This intermediary approach simplifies the overall mechanism compared to direct genetic modification while achieving reliable limitation of aberrant AR isoforms
Solution Approach 2:
The patent applies preliminary action by incorporating a stable 5' UTR region into the oligonucleotide design before administration. This 5' UTR is engineered to contain elements that enhance stability and promote efficient translation, ensuring that the oligonucleotide maintains sufficient half-life and concentration to effectively modulate splicing. This preliminary optimization of stability and expression reduces the complexity of dosing and administration while ensuring reliable therapeutic effect
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
The administration of SSOs effectively reduces the expression of AR and EGFR in cancer cells, leading to decreased proliferation and colony formation in prostate cancer cells, including those derived from African American patients. This approach provides a novel therapeutic strategy to address prostate cancer disparities and improve treatment outcomes for aggressive disease.
Implementation Method 1
a sequence complementary to the region comprising the 5' splice site of Exon 1 or Exon CE3 of the androgen receptor (AR)
Implementation Method 2
a sequence complementary to the region comprising exon 16 or exon 18 of the epithelial growth factor receptor (EGFR)
Data Source
AI summary
The present disclosure provides methods and compositions for the treatment of cancer. In some aspects, the present disclosure provides splice-switching oligonucleotides that downregulate AR or EGFR expression and methods of using these splice-switching oligonucleotides to treat cancer.