Most people with breast and other cancers die not from the primary tumor but from metastasis, when the cancer spreads throughout the body. Researchers have developed a compound that blocks the actions of a metastasis-causing protein, potentially reducing the spread of breast cancer.
Metastatic breast cancer – also called metastases, secondary tumors or secondaries – occurs when cancer cells break away from the original tumor and travel through the blood or lymphatic system to another part of the body, commonly the bones, lungs, brain, or liver.
Some cancers are more likely to metastasize than others, with research suggesting that specific genes or proteins are involved in the process. One such protein, S100A4, is expressed in metastatic cancers and has been associated with the premature death of people with cancers of the breast, bladder, pancreas, prostate, esophagus, lung and stomach. Rather than directly causing tumor growth, S100A4 has been shown to activate metastasis pathways in the body.
Now, a new study by researchers at the University of Liverpool, UK, and Nanjing Medical School in China looked closely at S100A4 and may have discovered a way to block its production, reducing the likelihood that the cancer will spread.
“As a general rule, cancer that has spread is treated with chemotherapy, but this treatment can rarely be given without severely harming or becoming 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 of cells from the highly metastatic and incurable type of breast cancer that doesn’t have any of the three commonly found receptors for the hormones estrogen and progesterone and the protein 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 was to identify a compound that inhibited the binding of protein S100A4 with calcium and prevented the metastatic pathway from commencing. A library of 2,400 compounds from Cancer Research UK was screened, and one compound, CT070909, was found to inhibit over 90% of S100A4 binding. Because CT070909’s molecular composition made it relatively insoluble, the researchers synthesized a structurally simpler compound, US-10113.
Testing US-10113 on the model systems, the researchers found it was “moderately weak” at inhibiting S100A4 binding. To improve the efficiency of US-10113, the researchers chemically coupled it to thalidomide, a type of targeted cancer drug used to treat myeloma, a type of blood cancer. Thalidomide stops cancer cells from dividing and growing, stops cancers from creating the blood supply they need to be able to grow, and stimulates some of the immune system cells to attack cancer cells.
They found that the combined thalidomide-US-10113 compound specifically eliminated S100A4 in rat and human TNBC cells, with a nearly 20,000-fold increase in efficiency compared to US-10113 alone. They saw few signs of toxicity.
“This is an exciting breakthrough in our research,” said Gemma Nixon, another of the study’s corresponding authors. “We now hope to take the next steps and repeat this study in a large group of animals with similar metastatic cancers so that the efficacy and stability of the compounds can be thoroughly investigated and, if necessary, improved by further design and syntheses, prior to any clinical trials.”
The researchers say their findings demonstrate proof-of-principle of a chemotherapeutic approach to selectively inhibit cancer metastases. Moreover, because the protein S100A4 is present in different kinds of cancers, it may lead to the development of a treatment for more than breast cancer.
“Significantly, this particular protein we’re investigating occurs in many different cancers, which could mean this approach may be valid for many other commonly occurring human cancers.”
The study was published in the journal Biomolecules.
Source: University of Liverpool
