Extracellular vesicles (EVs) filled with customizable anti-cancer antisense oligonucleotides (ASOs) have been shown to inhibit cancer growth.
Lung cancer, particularly Non-Small Cell Lung Cancer (NSCLC)—the most prevalent type in non-smoking patients—remains one of the leading causes of cancer-related deaths and the second most diagnosed cancer worldwide. The swift rise of drug resistance mechanisms due to mutations in cancer cells is significantly outpacing the development of new small molecule drugs. This pressing issue highlights the urgent need for a new, customizable, safe, and efficient anti-cancer treatment that can be designed, tested, and validated quickly.
A research team led by Assistant Professor Minh Le from the Institute for Digital Medicine (WisDM) and the Department of Pharmacology at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), has successfully illustrated that tiny particles released from cells, like red blood cells, can be repurposed as platforms for delivering antisense oligonucleotide (ASO) molecules designed to target cancer cells in the lungs, thus impeding cancer progression. This study was a collaboration with the Cancer Science Institute of Singapore (CSI Singapore) at NUS, the Agency for Science, Technology and Research (A*STAR), the National Cancer Centre Singapore (NCCS), and Duke-NUS Medical School.
Asst Prof Minh Le stated, “Mutant Epidermal Growth Factor Receptors (EGFRs) are the primary drivers of lung cancer in the Asian population. Consequently, we concentrated on targeting lung cancer associated with mutant EGFR. Currently, treatment involves drugs called tyrosine kinase inhibitors that inhibit the mutant EGFR protein to halt cancer advance. However, as cancer cells may mutate further and resist these drugs, we aimed to discover a more effective targeting approach.”
In their study published in eBioMedicine, the authors explored ASOs as a means to tackle the challenge of drug resistance and to advance precision medicine. Precision medicine focuses on customizing treatment to fit individual patients and their specific conditions, as opposed to a generalized approach. ASOs are capable of binding to particular segments of ribonucleic acid (RNA) to prevent irregular activities. These ASOs can be readily redesigned to address various gene issues, which is essential given NSCLC’s tendency to develop resistance against tyrosine kinase inhibitors. Additionally, these ASOs can be tailored to target distinct mutations according to each patient’s cancer profile. Nevertheless, one drawback of ASOs is their rapid degradation in the bloodstream, leading to reduced concentrations at tumor sites. This issue could be addressed with an effective method to encapsulate and deliver the ASOs directly to the cancerous regions.
To accomplish this, the researchers utilized extracellular vesicles (EVs) derived from human red blood cells as natural carriers to transport the anti-cancer ASOs to the tumor locations. To enhance targeting, they engineered specific moieties onto the surface of the EVs aimed at the EGFR. This modification enabled the EVs to accurately localize to the cancer cells. Moreover, the ASO-loaded EVs demonstrated significant anti-cancer efficacy across various lung cancer models, including cells derived from patients. The unique design of the ASOs allowed them to inhibit mutant EGFR while sparing the normal receptors. They further confirmed that the ASO-loaded red blood cell-derived EVs had strong anti-cancer effects against drug-resistant cancer cells.
Associate Professor Tam Wai Leong, Deputy Executive Director of A*STAR Genome Institute of Singapore (A*STAR GIS) and a co-corresponding author on the study, remarked, “The innovative application of extracellular vesicles as a delivery system for nucleic acid therapeutics represents a potentially game-changing treatment option for malignancies. The capability to specifically target and eliminate mutant EGFR cancer cells while protecting normal cells will permit personalized treatment for individual patients. This is a substantial progression in addressing cancer drug resistance and enhancing personalized cancer therapy.”
Professor Goh Boon Cher, Deputy Director of CSI Singapore, Professor of Medicine at NUS Medicine, and one of the study’s authors, added, “This research is crucial in pioneering precise therapeutic RNA delivery to tumor cells to effectively target their weaknesses. It serves as proof of concept that can be broadly adapted to other cancer treatments.”
