Innovative aptamer-based approaches to specifically target DNA methylation in non-small-cell lung cancer
Worldwide Cancer Research
National Research Council
The development of effective therapeutics has become an unmet need to reduce non-small-cell lung cancer (NSCLC) patient’s mortality. DNA methylation is a key epigenetic modification regulating gene expression and its alteration is the most common molecular lesion in several cancers, including NSCLC. It thus offers an innovative therapeutic target to reprogram cancer malignant transformation. However, medical intervention has been limited to toxic, unspecific demethylating drugs. To overcome these limits, we addressed DNA methylation targeting by exploring nucleic acid aptamers, promising ligands with high affinity and specificity. We developed nuclease-resistant RNA aptamers able to bind and neutralize the major epigenetic player DNA methyltransferase (DNMT)1. In this project, we aim to demonstrate the therapeutic potential of these aptamers and develop effective, safe and clinically translatable approaches combining aptamers and theranostic nanovectors (tNVs) for NSCLC selective therapy. To this end, we will characterize the anti-DNMT1 aptamers (WP1) and design the optimal systems for their delivery evaluating two approaches: i) bispecific molecules containing anti-DNMT1 and NSCLC targeting aptamers (WP2); ii) tNVs loaded with anti-DNMT1 aptamers and decorated with a NSCLC targeting aptamer (WP3). For NSCLC targeting, we will use our previously described GL21.T aptamer that binds and inhibits the NSCLC-expressed Axl receptor. Systems will be validated in 3D organoids (WP4).  This project will generate innovative demethylating agents and safe tools to deliver them to NSCLC, providing a paradigm shift in current therapies. In addition, it will afford important understanding of DNA methylation in NSCLC that can be exploited for other studies. Obtained results will permit the subsequent in vivo experimentation of our systems and their application to other types of cancers involving aberrant methylation. In the long-term, our technology may be implemented to increase the life expectancy and quality of NSCLC patients, thus representing an important milestone with great scientific and medical impact.
5.1 Pharmaceuticals