December 11, 2023

Most people with breast and other cancers die not from the primary tumor but from metastases, the spread of cancer throughout the body. Researchers have developed a compound that blocks the action of a protein that causes metastasis, potentially reducing the spread of breast cancer.

Metastatic breast cancer — also known as metastases, secondary tumors, or secondary tumors — occurs when cancer cells break away from the primary tumor and travel to another part of the body (usually the bones, lungs, brain, or liver) through the blood or lymphatic system.

Some cancers are more likely to metastasize than others, and research has shown that specific genes or proteins are involved in this process. One of these proteins, S100A4, is expressed in metastatic cancers and has been linked to premature death in patients with breast, bladder, pancreatic, prostate, esophageal, lung and stomach cancers. S100A4 has been shown to activate metastatic pathways in vivo rather than directly leading to tumor growth.

Now, a new study by researchers at the University of Liverpool in the UK and the Nanjing Medical School in China has taken a closer look at S100A4 and may have discovered a way to stop its production, thereby reducing the likelihood of cancer spreading.

“Typically, cancers that have spread can be treated with chemotherapy, but this treatment is rarely seriously harmful or toxic to the patient,” said Philip Rudland, one of the study’s corresponding authors. “The[importance]of our work was to identify a specific and important target to attack without toxic side effects.”

The researchers used rat and human model systems derived from highly metastatic and incurable breast cancer cells that do not have any of the three common receptors for estrogen and progesterone and human epidermal growth factor 2 (HER2). Known as triple negative breast cancer (TNBC), it accounts for 10% to 15% of all breast cancers.

The next step is to identify a compound that inhibits the binding of the protein S100A4 to calcium and prevents the initiation of the metastatic pathway. Screening of Cancer Research UK’s library of 2,400 compounds identified one compound, CT070909, which inhibits S100A4 binding by more than 90%. Because the molecular composition of CT070909 makes it relatively insoluble, the researchers synthesized a compound US-10113 with a simpler structure.

The researchers tested US-10113 on a model system and found it was “weaker” at inhibiting S100A4 binding. To increase the effectiveness of US-10113, the researchers chemically coupled it to thalidomide, a targeted cancer drug used to treat myeloma, a type of blood cancer. Thalidomide stops cancer cells from dividing and growing, stops the cancer from producing the blood supply it needs to grow, and stimulates some immune system cells to attack cancer cells.

They found that the compound thalidomide in combination with US-10113 specifically eliminated S100A4 in both rat and human TNBC cells with nearly 20,000-fold greater efficiency than US-10113 alone. They saw few signs of poisoning.

“This is an exciting breakthrough in our research,” said Gemma Nixon, the study’s other corresponding author. “We now hope to take the next step of repeating this study in a large cohort of animals with similar metastatic cancers, so that prior to any clinical trials, the compound’s efficacy and stability can be thoroughly studied and, if necessary, improved through further design and synthesis.”

The researchers say their findings demonstrate a proof-of-principle for a chemotherapy approach that selectively inhibits cancer metastasis. Furthermore, because the protein S100A4 is present in different kinds of cancer, it may lead to the development of treatments beyond breast cancer.

“Remarkably, the particular protein we’re studying is present in many different cancers, which could mean that this approach could be effective for many other common human cancers.”

The study was published in the journal Biomolecules.

source: University of Liverpool