Singapore Team Develops E8 Nanobody to Target Cancer Growth in Abdominal Lining

An experimental treatment targets the fluid around tumours

Scientists in Singapore have developed an experimental nanobody called E8 after analysing 397 samples spanning 21 primary cancer types and identifying two proteins that help cancer grow in the abdominal lining. Tests using tissue from 10 patients found that about 70% of tumour cells were eliminated, offering an early reason to pursue a treatment for people with few options.

The research addresses peritoneal metastasis, which happens when cancer spreads from an organ such as the stomach, colon or ovaries to the peritoneum, the membrane lining the abdominal cavity. Patients with this advanced condition have an average survival of less than nine months, according to the research team.

E8 is still in development. The team hopes to begin testing it in people within five years, with human safety, effectiveness and any benefit to survival still to be determined.

The National Cancer Centre Singapore led the collaboration with the Institute of Molecular and Cell Biology at the Agency for Science, Technology and Research, Singapore General Hospital and the National University of Singapore's Yong Loo Lin School of Medicine. The findings were published in September in the journal Molecular Cancer.

Why abdominal fluid became a treatment target

Ascites, an abnormal accumulation of fluid in the abdomen, is a typical feature of cancer that has spread to the peritoneum. The fluid can cause pain as it builds up. It also contains substances that help cancer cells survive and grow, making it part of the disease process rather than simply a troublesome symptom.

The Singapore researchers began investigating cancer spread to the abdominal membrane in 2016. Their work shifted attention towards the environment surrounding the tumours, including the fluid that bathes them.

Johnny Ong, the study's senior author and head of the department of sarcoma, peritoneal and rare tumours at Singapore General Hospital and National Cancer Centre Singapore, explained the approach:

"From here, there was proof of concept that we could target the fluid instead of the tumour cells to prevent the tumour from growing or spreading. What we proposed to do was add 'agents' into the water to break off the growth potential of the cancer cells," he said.

The practical idea is to interrupt the support that cancer receives from its surroundings. A tumour needs more than malignant cells to keep growing. Substances in nearby fluid can help sustain it, giving researchers another place to intervene.

Two proteins emerged from 397 samples

The team used molecular profiling to examine proteins and biological pathways across its dataset. Molecular profiling means measuring the biological components in a sample to understand which processes are active and which might be targeted with a drug.

PAI-1 and S100A10 emerged as two key drivers of tumour development in ascites. Proteins perform many jobs inside and around cells. In this research, identifying proteins that support cancer growth gave the scientists specific targets to investigate.

The researchers then selected one of the two proteins as the target for their experimental nanobody. E8 is designed to block a particular protein involved in supporting the cancer, rather than broadly attacking rapidly dividing cells as conventional chemotherapy does.

The dataset's coverage of 21 primary cancer types also reflects an important feature of peritoneal metastasis: cancers that begin in different organs can eventually spread into the same abdominal space. Studying that shared environment allowed the team to look for growth mechanisms across cancers with different starting points.

What E8 achieved in early tests

A nanobody is a small antibody fragment engineered to recognise a specific target. Antibodies work by attaching to particular molecules; researchers can use that ability to interfere with a protein's activity. E8 applies this approach to a protein linked to tumour growth in abdominal fluid.

The scientists tested the treatment in three systems: cancer cells grown in the laboratory, animal models and samples of advanced human abdominal cancer preserved in a hydrogel made from hyaluronic acid. A hydrogel is a material with a jellylike structure that holds water and can support tissue during experiments.

The human tissue tests used samples from 10 patients and found that about 70% of tumour cells were eliminated. The result concerns cells in experimental samples. Testing in patients is the next stage needed to measure how people respond to treatment.

Ong described the findings across the three experimental systems:

"Across all three, the therapy effectively suppressed tumour growth with minimal toxicity," he said.

The team expects a treatment aimed at a specific protein to have fewer side effects than conventional chemotherapy. Its early toxicity findings support further development, while clinical trials will assess the effects in people. For patients, the hoped for benefit is another way to control the cancer with a lower treatment burden.

Many patients cannot receive intensive treatment

Ong described hyperthermic intraperitoneal chemotherapy, usually shortened to HIPEC, as the best current treatment for the condition. It combines an operation to remove visible tumours with heated chemotherapy placed inside the abdominal cavity to attack remaining cancer cells.

Nine out of 10 patients are typically unsuitable for that approach, he said. Put another way, only about one in 10 is generally suitable, leaving a large majority needing other options.

E8 is being developed against that gap in care. The aim is to offer a targeted treatment for patients whose choices are limited, potentially reducing their dependence on repeated chemotherapy. How it would fit alongside existing treatments will depend on the results of clinical development.

The scale of the disease makes that gap substantial. Ong said more than 1.2 million cases of peritoneal cancer are diagnosed worldwide each year, with spread to the peritoneum occurring at some stage in about 70% of ovarian cancers, 40% of stomach cancers and 30% of colorectal cancers.

A patient's experience shows the need for more options

Yeow Ser Kiang, a retired accountant aged 76, was diagnosed with stage three ovarian cancer in 2017. She underwent surgery to remove her womb and ovaries, followed by 10 months of chemotherapy.

The cancer later returned and spread to her peritoneum. She subsequently underwent several operations and further rounds of chemotherapy, illustrating how treatment can become a repeated part of life after the disease returns.

Yeow donated ascites for the second phase of the research. Her contribution connects the laboratory work directly to the fluid that researchers are trying to understand and target.

Patient donations allow scientists to study material from the disease itself. In this project, ascites helped reveal the surroundings in which abdominal tumours grow, while preserved cancer tissue provided another setting in which to test the experimental treatment.

From research begun in 2016 to planned human testing

The team is now working on clinical grade development, preparing the treatment for possible use in human research. This stage connects experimental laboratory work with a product suitable for a clinical trial.

Ong said the researchers hope to begin the first trial in people within five years. He described the nanobody as the leading candidate in their effort to develop treatments for patients with limited choices.

The main milestones are:

• 2016: The team began investigating how cancer spreads to the abdominal membrane.
• 2017: Yeow was diagnosed with stage three ovarian cancer; she later donated ascites for the research.
• September: The findings were published in Molecular Cancer.
• Next stage: Clinical grade development, with a goal of beginning a first trial in people within five years.

The trial is intended to investigate safety and effectiveness in patients. That step will determine whether the encouraging laboratory findings can lead to a useful treatment for people living with peritoneal metastasis.

What the discovery could change for patients

Jimmy So, a professor in the department of surgery at NUS Medicine, described the discovery as encouraging because it could lead to treatment for a common and often deadly complication of abdominal cancers.

So expressed the goal for patients:

We hope this research can ultimately translate into better treatment options and renewed hope for patients facing this difficult condition.

The research brings together two parts of the problem: identifying what helps tumours grow in abdominal fluid and developing a drug designed to interrupt that process. The 397 samples helped identify the targets; the three experimental systems gave the team ways to test its proposed treatment.

For patients facing repeated surgery or chemotherapy, the goal is concrete: another treatment choice that controls tumour growth with fewer harmful effects. E8 has reached an early experimental milestone, and the planned move into human testing is the next step towards that goal.

Key Points

• Singapore researchers developed E8, an experimental nanobody targeting a protein that supports cancer growth in abdominal fluid.
• Analysis of 397 samples across 21 primary cancer types identified PAI-1 and S100A10 as key growth drivers.
• Tests using tissue from 10 patients found that about 70% of tumour cells were eliminated.
• The treatment suppressed tumour growth with minimal toxicity in laboratory cells, animal models and preserved human tissue, according to the team.
• Nine out of 10 patients are typically unsuitable for surgery combined with heated abdominal chemotherapy, according to Johnny Ong.
• The researchers hope to begin a first trial in people within five years.