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Synthetic biology used to target cancer cells while sparing healthy tissue

Christian Fernsby |
Synthetic proteins engineered to recognize overly active biological pathways can kill cancer cells while sparing their healthy peers, according to a study by researchers at the Stanford University School of Medicine.

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The customizable approach, which the researchers call RASER, relies on just two proteins: The first is activated in the presence of an "always on" growth signal often found in cancer cells, and the second carries out a researcher-programmed response, such as triggering the expression of genes involved in cell death.

Although the experiments were confined to cells grown in the laboratory, the researchers believe the results could lead to a new type of cancer therapy in which synthetic proteins deliver highly targeted and customizable treatments to sidestep the sometimes devastating side effects of current options.

Many cancers rely on a series of signals that originate from proteins called receptors that span the membrane of the cell.

These signaling cascades, or pathways, are used by healthy cells to grow in response to external cues, for example during development or recovery from injury.

Often, however, these receptor proteins are mutated or overexpressed in cancer cells in ways that render the receptor protein "always on," providing the cell with constant, unwarranted signals for growth.

The researchers focused on two receptors, EGFR and HER2 members of a family of receptors called the ErbB receptors that often drive the growth of brain, lung and breast cancers.

HER2, for example, is targeted by Herceptin in breast cancer.

Many common anti-cancer drugs, including Herceptin, work by blocking the cascade of signals triggered by receptor activation.

Unfortunately, however, these drugs have no way to discriminate between cancerous cells, in which the pathway is always activated, and healthy cells going about their business as usual.

That's where Lin and his team come in.Chung and her colleagues designed a synthetic protein consisting of two natural proteins fused together one that binds to active ErbB receptors and another that cleaves a specific amino acid sequence.

They then engineered a second protein that binds to the inner surface of the cell membrane and contains a customizable "cargo" sequence that can carry out specific actions in the cell.

When the first protein binds to an active ErbB receptor, it cuts the second protein and releases the cargo into the interior of the cell.

After several rounds of tinkering, the team saw that their RASER system, which stands for "rewiring of aberrant signaling to effector release," was highly specific for cancer cells dependent on ErbB receptor activity.

For their first test they chose to use a protein involved in triggering cell death as the RASER cargo.The team compared the RASER system to two therapies currently used for metastatic breast cancer a chemotherapy regimen and a drug that blocks ErbB activity on several types of cultured cells: breast and lung cancer cells in which the ErbB pathway was overly active; breast cancer cells in which ErbB activity was normal; and noncancerous breast and lung cell lines.

The researchers found that the traditional chemotherapy regimen of carboplatin and paclitaxel killed all the cells indiscriminately.

The effect of the ErbB pathway inhibitor on the viability of the cells varied and did not reliably correlate with ErbB pathway activity levels.

Only RASER specifically killed those cells in which the ErbB pathway was overly active while sparing those in which ErbB activity was normal.

While much work remains to be done to learn whether RASER is effective in human tumors, the researchers are excited about the possibilities of re-engineering the system to recognize other receptors mutated in cancers and swapping the cargos to achieve different outcomes.

Challenges include learning how best to deliver synthetic proteins into tumors and understanding how the immune system might react to RASER.

But Lin is optimistic.


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