Trojan Horse Traps and Destroys Drug-Resistant Cancer Cells

Written By Mark

Cancer cells can become resistant to treatment, and doctors don’t know when, where, or what resistance might emerge, leaving them one step behind cells that quickly evolve to outwit new treatments.

In this field, a team of researchers led by Pennsylvania State University in the United States entered the race against cancer cells, and found a way to anticipate events and eliminate the tumor before it begins to resist.

Why do modern cancer drugs fail?

Modern personalized cancer drugs often fail, not because the treatments aren’t good, but because of the inherent diversity and heterogeneity of cancer, said Justin Pritchard, a professor of biomedical engineering and lead researcher on the paper.

If the initial treatment is effective, eventually resistance develops and the drug stops working, allowing the cancer to return. Doctors then find themselves back at square one, repeating the process with a new drug until resistance reappears. The cycle escalates with each new treatment until there are no other options left.

According to the Eurek Alert website, researchers wondered if they could anticipate events and eliminate resistance mechanisms before cancer cells had a chance to develop and appear unexpectedly.

Trojan horse to eliminate cancer cells

The researchers created a genetic circuit that turns cancer cells into a “Trojan horse,” causing neighboring drug-resistant cancer cells to be killed. They tested the method in the lab on human cells and in mice as a proof of concept, and the new method overcame a wide range of forms of resistance.

The genetic circuit that scientists created is based on genes that are turned on and off as needed. The first gene modifies cells and creates a type of resistance that can be turned off at the right time. When the gene works, some cells become resistant to drugs, and then the patient is given a drug that can kill the non-resistant cancer cells.

After eliminating the non-resistant cells using the conventional drug, the resistant cells remain; these are the genetically modified cells and the cancer cells. The resistant cells that were modified by humans grow and impose their control, and a small number of resistant cancer cells remain that cannot develop as a result of the control of the modified cells.

In the second stage, the Trojan horse stimulates a suicide gene in the modified cells to produce a toxin that kills the modified cells and neighboring resistant cancer cells.

This mechanism was tested on non-small cell lung cancer cells that carry a genetic mutation that can be targeted by commercially available drugs.

An idea born out of frustration

The research results were published July 4 in the journal Nature Biotechnology, and the researchers have filed a provisional patent application for the technique described in the paper. “This idea was born out of frustration,” said lead researcher Justin Pritchard. “We’re not doing a bad job of developing new cancer drugs, but how can we think of potential treatments for advanced cancers? I love the idea that we can use the inevitability of tumor evolution against itself.”

The team first simulated tumor cell populations, using mathematical models to test the concept. They then cloned each gene, packaged it separately into viral vectors, and tested its functions individually in human cancer cell lines. They then linked the two genes together into a single circuit and tested them again. Once the circuit was shown to work in the lab, the team repeated the experiments in mice.

“The beauty is that we can target cancer cells without knowing what they are, and without waiting for them to grow or develop resistance, because by that point it’s too late,” said Scott Lehau, a postdoctoral researcher in biomedical engineering and lead author of the paper.

Researchers are currently working on how to translate this genetic circuit so that it can be safely and selectively delivered to growing tumors and, eventually, to metastatic disease.