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Preclinical Screening of Splice-Switching Antisense Oligonucleotides in PDAC Organoids
Abstract:
Aberrant alternative splicing is emerging as a cancer hallmark and a potential therapeutic target. It is the result of dysregulated splicing factors or genetic alterations in splicing-regulatory cis -elements. Targeting individual altered splicing events associated with cancer-cell dependencies is a potential therapeutic strategy, but several technical limitations need to be addressed. Patient-derived organoids (PDOs) are a promising platform to recapitulate key aspects of disease states and to facilitate drug development for precision medicine. Here, we report an efficient antisense-oligonucleotide (ASO) transfection method to systematically evaluate and screen individual splicing events as therapeutic targets in pancreatic ductal adenocarcinoma (PDAC) organoids. This optimized delivery method allows fast and efficient screening of ASOs that reverse oncogenic alternative splicing. In combination with advancements in chemical modifications and ASO-delivery strategies, this method has the potential to accelerate the discovery of anti-tumor ASO drugs that target pathological alternative splicing.
Insights
Aberrant alternative splicing drives cancer and offers therapeutic targets. Researchers developed an efficient antisense oligonucleotide (ASO) method to screen ASO drugs in pancreatic cancer organoids, accelerating anti-cancer drug discovery.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Aberrant alternative splicing is a recognized hallmark of cancer, often caused by altered splicing factors or genetic changes in regulatory elements.
- Targeting cancer-specific splicing events presents a therapeutic strategy, but faces technical challenges in drug development.
- Patient-derived organoids (PDOs) offer a valuable model for disease states and precision medicine drug development.
Approach:
- Developed an efficient antisense oligonucleotide (ASO) transfection method for pancreatic ductal adenocarcinoma (PDAC) organoids.
- This method enables systematic evaluation and screening of individual splicing events as therapeutic targets.
- Optimized delivery facilitates rapid screening of ASOs designed to reverse oncogenic alternative splicing.
Key Points:
- The study presents a novel ASO transfection technique for PDAC organoids.
- This approach allows for efficient screening of therapeutic targets related to alternative splicing.
- The method addresses technical limitations in targeting aberrant splicing in cancer.
Conclusions:
- The optimized ASO delivery method accelerates the screening of anti-tumor ASO drugs.
- This technique has the potential to advance the development of drugs targeting pathological alternative splicing.
- Combines advancements in ASO chemistry and delivery for precision cancer therapy.
