Image courtesy of PIT Bioinformatics Group.
Picture this: a group of ancient warriors hiding inside a massive wooden horse, ready to infiltrate a fortified city. When the unsuspecting guards bring the horse inside, the warriors leap out and take over from the inside. This is the story of the Trojan Horse, and believe it or not, postdoctoral associate Fei Cao and associate professor James Hansen at the Yale School of Medicine Department of Therapeutic Radiology have found a way to use this tactic against cancer cells with a groundbreaking new therapy.
The heroes in this story are called antinuclear antibodies (ANAs). Typically, these antibodies play a role in autoimmune diseases like lupus, where they mistakenly target the body’s own cells. However, researchers have repurposed these antibodies to infiltrate cancer cells and cause damage. One of the most remarkable examples of these is Deoxymab-3 (DX3). This antibody is designed to sneak into the nuclei of cancer cells, where it can enact its destructive potential.
Cancer cells often have multiple defenses that make them difficult to treat. Many standard therapies rely on targeting specific surface markers to identify and attack cancer cells. However, this approach can be limiting, particularly against aggressive tumors that lack these markers. DX3 associates with the nucleoside (essentially a nucleotide without the traditional phosphate group) salvage pathway—a recycling process that converts nucleosides back into nucleotides for cellular processes. DX3 first enters the cell via nucleoside transporters. As the nucleoside is brought into the cell for repurposing, DX3 successfully bypasses the cell membrane and nuclear membrane, entering even the most secure cancer cells.
Once the DX3-nucleoside transporter complex is inside the nucleus, it lures an enzyme known as cathepsin B (CatB) into the nucleus. Under normal conditions, CatB resides in the cytoplasm, where it helps break down cellular waste. However, when DX3 brings CatB into the nucleus, the researchers hypothesize a self-defense mechanism is triggered due to the fact that DX3 itself is toxic to the cancer cells.
In addition to DX3, the scientists developed a next-generation weapon called an antinuclear antibody-drug conjugate (ANADC). “This approach combines DX3 with a powerful drug, linked by a chemical fuse that CatB can sever,” Cao said. When DX3 infiltrates the cancer cell’s nucleus and draws CatB in, the enzyme activates ANADC precisely where it is needed by cleaving the link between the drug and DX3, delivering a targeted attack on the cancer cells. However, if CatB is blocked, ANADC loses its effectiveness, emphasizing the enzyme’s critical role in this therapy.
What sets ANADC apart is its tumor-agnostic nature, meaning that it has the potential to address a wide range of cancers, regardless of their individual characteristics. Unlike traditional treatments that depend on specific markers, ANADC targets the DNA and nucleosides released by dead or dying tumor cells.
Researchers have tested this innovative strategy against brain cancer modeled in mice with impressive results. One of DX3’s standout features is its ability to cross the blood-brain barrier (BBB), a major obstacle for many therapies. The BBB, a filter-like membrane between the blood and brain, protects the brain from harmful substances but also prevents most drugs from reaching it. DX3 uses nucleoside transporters to navigate this barrier, allowing it to potentially treat difficult-to-reach brain tumors like gliomas.
In laboratory studies and mouse models, ANADC has demonstrated its ability to penetrate cancer cells effectively, leading to substantial tumor destruction. It not only slows tumor growth but also extends survival rates without harming healthy tissues. This is a significant advancement, as many conventional treatments, such as chemotherapy, often damage healthy cells and lead to severe side effects.
Cao and Hansen’s work offers a novel approach to cancer therapy, transforming antinuclear antibodies into effective agents that can infiltrate and destroy cancer cells from within. By leveraging DX3’s ability to lure CatB into the nucleus, this therapy can potentially target a wide array of cancers, even those resistant to current treatments. “Cancers such as triple-negative breast cancer do not have normal cell receptors, so the world can benefit from this type of therapy,” Cao said. The capability to cross the BBB and specifically target brain tumors further enhances its potential.
The DX3 antibody is currently patented and already listed in clinical trials with researchers having high hopes of replicating in humans the promising results seen in mice. This innovative strategy offers new hope in the ongoing fight against cancer, with the potential to revolutionize the way we treat this complex disease and bring us one step closer to a cure. Watch out, tumor cells! The cure is right behind you.