Combination strategies enable simultaneous activation and silencing of key target genes to correct molecular pathways in pancreatic cancer.
For the first time, scientists have designed combination therapies of small nucleic acid therapeutics based on the specific molecular characteristics of a tumor. These novel therapies work in an opposite but complementary way to regulate gene expression. This innovative approach, tested in pre-clinical models of pancreatic ductal adenocarcinoma (PDAC), shows superior anti-cancer effects compared to single nucleic acid therapies, offering the potential of flexible, precise, and personalized cancer treatments.
“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,” explains Dr. Peng Ling, Research Director at the French National Scientific Research Center (CNRS).
“In principle, the same approach could also be adapted if the molecular characteristics of a tumor change during the course of the disease,” she adds.
Nucleic acid therapies in the era of precision and personalized medicine
Cancer is a complex disease involving alterations to multiple genes at the same time. To further complicate matters, gene alterations can vary between patients and change over time. This moving target makes treatment design challenging. Currently, most nucleic acid therapies offer only a single target strategy. This means they act only in one direction, to either turn off oncogenes or turn on tumour suppressor genes, but not both simultaneously.
To address this, scientists use nucleic acid therapies: nucleotide sequences that target and interfere with gene expression. Of these therapies, small interfering RNA (siRNA) and small activating RNA (saRNA) are of particular interest. siRNA silences gene expression, while saRNA activates gene expression.
In a novel approach, the team use a combination of these to simultaneously turn on tumour suppressor genes while turning off oncogenes, offering a flexible, precise, and personalized approach to tackle a multitude of gene expression complexities in cancer.
“In this way, we aim to address two sides of the molecular imbalance that contributes to cancer,” remarks Ling.
Selecting molecular characteristics for simultaneous gene activation and silencing
At the onset of the study, Ling says the team wanted to address two key questions in this field: “Can we design RNA-based treatments that address several cancer-related abnormalities at the same time? And can we select the right combination according to the molecular characteristics of each patient’s tumor?”
To answer this, they embarked on a proof-of-concept study in pancreatic ductal adenocarcinoma-one of the deadliest cancers, driven by a multitude of complex gene alterations. Ling explains their approach: “In very simple terms, we first identify what is going wrong in the tumor and then choose the appropriate RNA molecules to turn cancer-promoting genes down and tumor-suppressing genes back up, simultaneously, for concerted action.”
To do this, the team first selected key target genes driving the disease. To develop nucleic acid therapies against these, they analysed RNA transcript readouts and associated protein profiles in forty-five patient-derived pancreatic cancer models. This identified gene abnormalities in each tumour, enabling nucleic acid therapies to be designed against these. The researchers then evaluated the efficacy of these therapies in cell cultures, organoids, and tumour xenografts (tumours implanted into mice).
The novel combination therapies reduced cell proliferation, tumour growth, and progression more effectively than single nucleic acid options. This synergistic dual action was proven in the tumor models of increasing complexity: cell cultures, organoids, and tumour xenografts. Efficacy findings in mouse models with transplanted tumours confirms the translatability of combination therapies from in vitro to alive models.
Ling explains how the combination therapies offer a precise and personalized medicine strategy.
“Importantly, different tumor models responded best to different RNA combinations. At the same time, some combinations worked well in several tumor models that shared similar molecular characteristics. This suggests that, in the future, RNA combinations might be selected either for an individual patient’s tumor or for groups of patients whose tumors have similar molecular features.”
The future of nucleic acid therapy
This proof-of-concept study holds promise for tailoring nucleic acid therapies for precise and personalized cancer treatments, but has limitations. Firstly, only a few target genes were investigated in one type of cancer: future studies will need to evaluate more target genes in different cancers.
The researchers also acknowledge the challenge of delivering therapies to cells for long enough to produce effects, and they identify optimization of delivery systems as a key area of future research. Furthermore, although patient-derived tumor models were used, we do not know yet how effective these therapies would be in the real human tumour environment.
If these limitations are addressed in future studies, combination nucleic acid treatments could transform cancer therapies.
“The broader vision is to move beyond the idea of “one drug for one target” toward combinations of programmable RNA treatments that can be matched to the molecular characteristics of an individual patient’s disease,” explains Ling.
References: J. Wu et al., Concerted Action of Targeted Nucleic Acid Therapeutics as Flexible, Precision and Personalized Cancer TreatmentAdvanced Science (2026), DOI: 10.1002/advs.76840
Featured Image Credit: Konstantin Kolosov via Pixabay
Source: www.advancedsciencenews.com
