Customized Antisense Oligonucleotides Could Further Lung Cancer Treatment

New study findings conducted in collaboration with the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS); the Agency for Science, Technology and Research (A*STAR); the National Cancer Centre Singapore; and Duke-NUS Medical School, announced that repurposing nano-sized particles released by cells could serve as a delivery platform to carry molecules targeting cancer cells in the lungs, suppressing lung cancer progression.¹

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“This work is instrumental in breaking new ground for precise delivery of therapeutic RNA to tumor cells to destroy them by targeting their vulnerabilities. It is a proof of concept that can be broadly applied in other areas of cancer treatment,” said study author Goh Boon Cher, PhD, deputy director of CSI Singapore and professor of medicine at NUS Medicine, in a news release.¹

According to the American Cancer Society (ACS), an estimated 234,580 individuals in the US will be diagnosed with lung cancer in 2023, which is 11.7% of all new cancer cases. Additionally, ACS estimated that 125,070 individuals in the US will die from lung cancer, which is 20.4% of all cancer deaths.²

Non-small cell lung cancer (NSCLC) is a subtype of lung cancer that accounts for 80% of all lung cancer cases, with a poor 5-year survival rate.³ This marks NSCLC as the most common subtype of cancer contracted by individuals that do not smoke and is the second most diagnosed cancer globally, according to the study authors.¹

Individuals diagnosed with NSCLC are commonly treated with tyrosine kinase inhibitors (TKIs), which are the current standard therapy for the disease that bears EGFR mutations. However, study authors noted that there is a need for additional treatments, as TKIs are connected to severe toxicities due to unspecific inhibition of wild-type (WT) EGFR, along with drug-acquired resistance caused by the emergence of new EGFR mutations.³

“Mutant EGFRs are the most common driver of lung cancer among the Asian population. Therefore, we focused on targeting lung cancer caused by the mutant EGFR. Currently, drugs known as TKIs are the standard of treatment, and they work by inhibiting the mutant EGFR protein to stop cancer progression. As the cancer cells may further mutate and resist these drugs, we sought to find a more effective way to target the cancer,” said Minh Le, T.N. LE, PhD, from the Institute for Digital Medicine and Department of Pharmacology at the NUS Yong Loo Lin School of Medicine, in a press release.¹

The researchers assessed the use of customized antisense oligonucleotides (ASOs) as a new therapeutic strategy to selectively target activating mutations in the EGFR gene to overcome drug resistant mutations.³

The study authors noted that ASOs are molecules that stick to a precise part of a ribonucleic acid (RNA) and constrain irregular activity. Due to the flexibility of ASOs, they can be customized to target unique mutations based on the cancer profiles in each patient, which can fix problems in different genes. However, ASOs are easily damaged in the bloodstream, which can cause diluted treatment to the site of the tumor. This can be fixed with a method to hold the ASOs, directly delivering them to the tumor site, according to the release.¹

In the study, the researchers applied extracellular vesicles (EVs) retrieved from human red blood cells to serve as natural carrier to deliver the anti-cancer ASOs to the tumor site. Study authors noted that this process displayed an effective anti-cancer result in different models of lung cancer, which allowed the suppression of mutant EGFR and did not affect the normal EGFR.¹

“The innovative use of extracellular vesicles as a delivery vehicle for nucleic acid therapeutics added a potentially powerful treatment modality for treating malignancies. The ability to precisely eliminate mutant EGFR cancer cells while sparing normal tissues will enable customized treatment for individual patients. This is a significant step towards addressing cancer drug resistance and advancing the application of personalized cancer medicine,” said co-corresponding author of the study Tam Wai Leong, PhD, BSc, deputy executive director of A*STAR Genome Institute of Singapore, in the press release.¹

REFERENCES

1. Scientists use microcellular drones to deliver lung cancer-killing drugs. EurekAlert!. News release. November 11, 2024. Accessed November 12, 2024. https://www.eurekalert.org/news-releases/1064368.

2. Key Statistics for Lung Cancer. American Cancer Society. January 29, 2024. Accessed November 12, 2024. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html#:~:text=Lung%20cancer%20(both%20small%20cell,men%20and%2059%2C280%20in%20women).

3. Customized design of antisense oligonucleotides targeting EGFR driver mutants for personalized treatment of non-small cell lung cancer. eBioMedicine. News release. October 2024. Accessed November 12, 2024. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(24)00392-X/fulltext.