By Roger Meissen | Bond LSC
Treating lung cancer is tricky business.
Not only is it more deadly than other cancers due to late diagnosis, but resistance also grows quickly against its few existing treatments and therapeutics, so new approaches are vital to higher survival.
That’s especially true for one subset of lung adenocarcinoma (LUAD), and University of Missouri scientists have shown promising progress toward understanding what drives this cancer growth and developing a way to treat it.
Using aptamers — short strands of DNA or RNA — a team from the Donald Burke lab at MU’s Bond Life Sciences Center decreased tumor growth and viability in mice by binding it with mutated receptors on the surface of cancer cells in this oncogene positive of non-small cell lung cancer. Their work published in Nature’s Precision Oncology.
“The aptamer folds up into a 3D structure that actually targets these mutated surface receptors that are always on, always signaling, in these cancer cells,” said Brian Thomas, lead author and Mizzou MD-PhD candidate in the Burke lab. “That binding event prevents growth and slashes proliferation to prevent the survival of these cancer cell lines.”
Intended to contribute to the federal Cancer Moonshot that aims to reduce cancer mortality 50 percent or more by 2050, the lab’s developments show promise for a novel therapeutic for a difficult to treat type of cancer. Current first line treatments involve tyrosine kinase inhibitors (TKIs) that prevent mutated epidermal growth factor receptor (EGFR) in LUAD from causing uncontrolled cell growth. However, resistance to these drugs typically grows in 12-18 months, and second- and third-line treatments frequently don’t work.
“EGFR is present on cell surfaces, but mutant EGFR is only present on cancer. This receptor is always on because of these mutations, and they cause uncontrolled growth, progression and cancer survival,” Thomas said. “Essentially, we show that when our anti-EGFR reagent, our aptamer, binds with this receptor, EGFR, it competed with FDA-approved antibodies — specifically cetuximab —commonly used to treat types of cancer including colorectal cancer.”
Because this aptamer competed with a clinically relevant antibody, Thomas and colleagues thought that it might have anti-cancer properties in certain cancers.
Aptamers aren’t a new technology. The small molecules of DNA or RNA were first considered by scientists in 1990 due to their potential to selectively bind to very targeted areas on a cell, and they show promise as therapeutics or as vehicles to deliver cancer drugs and treatments for other diseases. Their promise lies in being relatively inexpensive, readily scalable and their relatively low level of toxicity since the body’s adaptive immune system doesn’t recognize them.
Only two aptamers have been approved for use by the Food and Drug Administration (FDA) in the past 35 years — one in 2004 and one in 2023— but both provide treatment for an eye condition called macular degeneration. This low number of FDA-approved treatments from aptamers boils down to a few challenging shortcomings to the molecules.
“Their two primary limitations are that since aptamers are DNA or RNA, they can get chopped up and disposed of by things in the body called nucleases, and that they are very small,” Thomas said. “So, instead of staying in the body, they will be filtered out by the kidneys and essentially peed right out, which is why we injected our (aptamer) reagent directly into subcutaneous mouse tumors.”
Future research can be targeted at overcoming these obstacles. Thomas said coupling the aptamer to make it larger and exploring different delivery methods could make a treatment like this viable.
“We can potentially make the aptamer bigger by appending it to some larger molecule that that can keep it in the body and keep it from getting filtrated, he said. “For lung cancer, researchers could also explore how to aerosolize it. Getting a patient to inhale it through an intranasal drip or nebulizer treatment, we can get high doses of oligonucleotides into the lung that way.”
Read more about this work in Thomas’ Behind the Paper article on Nature’s website.
Collaborators on this study include Bond LSC principal investigator Donald Burke and former Burke lab member David Porciani as well as Bond LSC principal investigator Trupti Joshi, graduate student Sania Awan of Mizzou’s Institute for Data Science and Informatics and Mizzou NextGen Precision Health researcher Mark Daniels.