Scientists have designed combination therapies of small nucleic acid therapeutics based on specific tumor characteristics, utilizing opposite yet complementary mechanisms to regulate gene expression in pancreatic cancer, Advanced Science reported. Tested in pre-clinical models of pancreatic ductal adenocarcinoma, the approach delivers superior anti-cancer effects compared to single nucleic acid therapies by simultaneously turning off oncogenes and turning on tumor suppressor genes.
Targeting Pancreatic Ductal Adenocarcinoma With Dual RNA Action
Cancer involves alterations to multiple genes at once, and these gene changes vary between patients and shift over time. Most nucleic acid therapies currently offer only a single target strategy, acting in one direction to either turn off oncogenes or turn on tumor suppressor genes. To address this limitation, researchers combined small interfering RNA, which silences gene expression, with small activating RNA, which activates it.
The research team identified key target genes driving pancreatic ductal adenocarcinoma by analyzing RNA transcript readouts and associated protein profiles across 45 patient-derived pancreatic cancer models. They then evaluated the efficacy of these therapies in cell cultures, organoids, and tumor xenografts implanted into mice. The dual action successfully reduced cell proliferation, tumor growth, and progression more effectively than single nucleic acid options.
Personalizing RNA Combinations For Patient Tumors
Different tumor models respond best to specific RNA combinations, while certain combinations work well across multiple tumor models sharing similar molecular characteristics. “What our study demonstrates is the potential of a different way of designing treatment: rather than giving every patient the same treatment, we could potentially select an RNA combination according to the molecular characteristics of the patient’s tumor,” Peng Ling, Research Director at the French National Scientific Research Center, explained in Advanced Science. Ling added that the approach could also be adapted if a tumor’s molecular characteristics change during the course of the disease.
The proof-of-concept study, detailed in Advanced Science, investigates only a few target genes in one type of cancer. Future research must evaluate more target genes across different cancers and optimize delivery systems to maintain therapy inside cells long enough to produce lasting effects.
Frequently Asked Questions About Combination Nucleic Acid Therapies
How do siRNA and saRNA work together against cancer?
Small interfering RNA silences cancer-promoting oncogenes by turning them down, while small activating RNA turns tumor-suppressing genes back up. Using both simultaneously allows the treatment to address two sides of the molecular imbalance contributing to cancer.
What types of tumor models were used in the preclinical testing?
Researchers tested the combination therapies in cell cultures, organoids, and tumor xenografts where tumors were implanted into mice. These models originated from 45 patient-derived pancreatic cancer samples.
What are the primary challenges remaining for these treatments?
Scientists must investigate more target genes in different cancers and solve the challenge of delivering therapies to cells long enough to produce therapeutic effects. Researchers also need to confirm how effective these therapies will be in the actual human tumor environment.
The broader vision of the research moves beyond the standard model of one drug for one target toward programmable RNA treatments matched to an individual patient’s disease.
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