Stanford researchers have developed synthetic proteins that can rewire cancer cells in a lab dish by co-opting critical disease-associated pathways
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.
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.
“We’re effectively rewiring the cancer cells to bring about an outcome of our choosing,” said Michael Lin, MD, PhD, associate professor of neurobiology and of bioengineering. “We’ve always searched for a way to kill cancer cells but not normal cells. Cancer cells arise from faulty signals that allow them to grow inappropriately, so we’ve hacked into cancer cells to redirect these faulty signals to something useful.”
A paper describing the work was published May 2 in Science. Lin is the senior author. Former graduate student Hokyung Chung, PhD, is the lead author.
Signals from receptors
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.
“We haven’t had a drug that can tell the difference between a pathway signaling normally and one that is abnormally active,” Lin said. “We knew we needed a better strategy, a more rational way of treating cancer. But we’ve not had a way to do it until recently.”
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.
“When the receptor protein is always on, as it is in cancer cells, the released cargo protein accumulates over time,” Chung said. “Eventually enough accumulates to have an effect on the cell. In this way, the system produces an effect only in cancer cells, and we can convert the always-on state of the receptor into different outcomes through the choice of cargo protein.”
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.
Killing only overactive cells
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.
We knew we needed a better strategy, a more rational way of treating cancer. But we’ve not had a way to do it until recently.
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.
“We have so much more information now about cancer genomics, signaling and how cancer cells interact with the immune system,” Lin said. “It’s finally becoming practical to combine this knowledge with synthetic biology approaches to tackle some of these pressing human health problems. RASER is both customizable and generalizable, and it allows us for the first time to selectively target cancer cells while sparing normal signaling pathways.”
The Latest on: Synthetic proteins
via Google News
The Latest on: Synthetic proteins
- Why Bill Gates Thinks People Should Only Be Eating Synthetic Beefon February 23, 2021 at 2:04 pm
This is why Bill Gates thinks people should only be eating synthetic beef. With Impossible Foods and Beyond Meat growing, Gates thinks we should cut out meat.
- C-reactive protein is a predictive factor for complications after incisional hernia repair using a biological meshon February 23, 2021 at 5:46 am
The introduction of biological or absorbable synthetic meshes has provided an alternative to conventional repair for incisional hernia. The ability to predict the development of complications after ...
- Will alternative proteins become the norm, and what will it mean for Aotearoa?on February 22, 2021 at 8:14 am
Depending on who you ask, New Zealand’s meat sector is either facing imminent extinction due to the rise of alternative proteins, or is uniquely positioned to capture wealthy customers wanting more ...
- Bill Gates roasted for saying rich countries should eat ‘100% synthetic beef’on February 20, 2021 at 8:10 am
His solution: the richest countries should hold the beef, period, and switch to plant-based or synthetic proteins. “I do think all rich countries should move to 100% synthetic beef,” Gates told ...
- New artificial membranes enable better understanding of membrane proteinson February 20, 2021 at 2:32 am
A new artificial membrane helps researchers understand proteins in human cell membranes. The membrane rim is made of a detergent, with a center made of lipid molecules found in biological membranes, ...
- Pore-like proteins designed from scratchon February 18, 2021 at 11:12 am
Ian Haydon/Institute for Protein Design New beta-barrel proteins fold spontaneously and embed into synthetic lipid membranes In a milestone ...
- Bill Gates to Beef Eaters: Shift to Synthetic Option to Fight Climate Changeon February 18, 2021 at 4:52 am
I don’t think the poorest 80 countries will be eating synthetic meat. I do think all rich countries should move to 100% synthetic beef, Gates told the MIT Technology Review.
- Bill Gates thinks we should start eating ‘100% synthetic beef’on February 16, 2021 at 12:19 pm
Bill Gates believes the wealthiest countries should switch to eating “100% synthetic beef” in order to help combat climate change. The second-richest man in the world floated his ideas ...
- How to get protein from natural products | Meg Unprocessedon February 16, 2021 at 12:17 pm
For people that want to boost their protein intake, protein powders are not always the healthiest way to go. SACRAMENTO, Calif. — Protein powders may seem like a simple solution to add more nutrients ...
- Bill Gates says rich countries should only eat beef which is syntheticon February 16, 2021 at 12:09 pm
The Microsoft founder’s new book offers a guide to tackling the climate crisis, with a focus on tech solutions ...
via Bing News