Synthetic biology used to target cancer cells while sparing healthy tissue – ScienceDaily

The customizable approach, which researchers call RASER, relies only on two proteins: the first is activated in the presence of a growth signal always present in the cancerous cells, and the second carries out a programmed response by the researcher, such as trigger the expression of genes involved in cell death.

Although the experiments were limited to cells grown in the laboratory, the researchers believe that the findings could lead to a new type of cancer treatment in which synthetic proteins would produce highly targeted and customizable treatments to avoid side effects sometimes devastating current options.

"We are effectively rewiring cancer cells to achieve the outcome of our choice," said Michael Lin, MD, PhD, badociate professor of neurobiology and bioengineering. "We've always been looking for a way to kill cancer cells, but not normal cells.Cancer cells come from faulty signals that allow them to develop inappropriately, so we've hijacked cancer cells to redirect these defective signals to somebody else. something useful. "

An article describing the work will be published on May 2 in Science. Lin is the main author. Hokyung Chung, Ph.D., former graduate student, is the main author.

Receiver signals

Many cancers rely on a series of signals from proteins called receptors acting on the cell membrane. These cells or signaling pathways are used by healthy cells to grow in response to external signals, for example during development or healing of an injury. However, often these receptor proteins are mutated or overexpressed in cancer cells so as to render the receptor protein "still active", providing the cell with constant and unjustified growth signals. The researchers focused on two receptors, EGFR and HER2 – members of a family of receptors known as ErbB receptors – that often result in the growth of cancers of the brain, lung and bad. HER2, for example, is targeted by Herceptin in bad cancer.

Many common anticancer drugs, including Herceptin, work by blocking the cascade of signals triggered by receptor activation. Unfortunately, these drugs have no way of distinguishing between cancer cells, in which the pathway is still activated, and healthy cells that look as if nothing has happened. That's where Lin and his team come in.

"We did not have a drug that could tell the difference between a normal signaling path and an abnormally active path," Lin said. "We knew we needed a better strategy, a more rational way to treat cancer, but we had not found a way to do it until recently."

Design a synthetic protein

Chung and his colleagues have designed a synthetic protein composed of two fused natural proteins – one that binds to the active ErbB receptors and another that cleaves a specific amino acid sequence. They then developed a second protein that binds to the inner surface of the cell membrane and contains a customizable sequence of "cargo" that can perform specific actions in the cell. When the first protein binds to an active ErbB receptor, it cuts the second protein and releases the cargo inside the cell.

"When the receptor protein is still active, as in cancer cells, the released cargo protein accumulates over time," Chung said. "In the long run, a sufficient amount accumulates to have an effect on the cell.This way, the system produces an effect only on the cancer cells and we can convert the state of the always active receptor into different results. choosing the cargo protein. "

After several do-it-yourself sessions, the team found that its RASER system, which stands for "rewiring of aberrant signaling for effector release," was highly specific for cancer-dependent cells. ErbB receiver activity. For their first test, they chose to use a protein involved in triggering cell death as RASER cargo.

Kill only the hyperactive cells

The team compared the RASER system with two commonly used treatments for metastatic bad cancer – a chemotherapy regimen and a drug that blocks ErbB activity – on several types of cells in culture: bad cancer cells and bad cancer cells. lungs in which the ErbB pathway was too active; bad cancer cells in which ErbB activity was normal; and non-cancerous bad and lung cell lines.

The researchers found that traditional chemotherapy with carboplatin and paclitaxel killed all cells indiscriminately. The effect of the ErbB pathway inhibitor on cell viability varied and was not reliably correlated with ErbB pathway activity levels. Only RASER specifically killed cells in which the ErbB pathway was too active, while sparing those in which ErbB activity was normal.

While much work remains to be done to find out if RASER is effective in human tumors, researchers are excited about the possibilities of reconfiguring the system to recognize other mutated receptors in cancers and to exchange them. cargo ships to get different results. Challenges include learning how to best administer synthetic proteins in tumors and how the immune system might respond to RASER. But Lin is optimistic.

"We now have a lot more information about cancer genomics, signaling and the interaction of cancer cells with the immune system," Lin said. "It has finally become practical to combine this knowledge with synthetic biology approaches to solve some of these human health problems.RASER is both customizable and generalizable.It allows us for the first time to selectively target cancer cells. while preserving normal signaling pathways. "