Researchers have developed an automated platform that they've used to screen thousands of drugs and identify those that can be used to interrupt the spread of melanoma, one of which they successfully trialed on mice. The approach could help identify promising drugs to treat metastatic cancers.
Metastatic cancers, particularly melanoma, continue to present a challenge because each tumor may have a unique microenvironment and respond differently to treatment. A particularly aggressive form of cancer, once melanoma has spread, its survival rate is low.
A feature of the metastatic process is the formation of invadopodia by tumor cells, specialized protrusions whose function is to degrade the extracellular matrix so that the cells can enter – or invade – new environments. Identifying drugs that target invadopodia is crucial to effectively preventing cancer spread, but currently, the ability to screen for these drugs is lacking.
All that might’ve changed with the development of "Invasion-Block," an automated, high-content screening platform that’s enabled researchers at the Centenary Institute in Australia to assess how well various drugs and compounds can prevent the spread of melanoma by targeting invadopodia.
“Melanoma is a tough opponent, often spreading rapidly and making it difficult to treat,” said Shweta Tikoo, the study’s corresponding author. “The key to finding better treatments lies in drug discovery, and this is where the ‘Invasion-Block’ tool plays a pivotal role.”
The researchers combined Invasion-Block with an automated image analysis pipeline adapted from astronomical sciences called Smoothen-Mask and Reveal (S-MARVEL), which was used to remove artifacts and substantially improve the quality of datasets of microscopic images of invadopodia.
They then screened 3,840 drugs in two FDA-approved compound libraries for their ability to inhibit invadopodia formation in melanoma cells and found that the most effective compounds were kinase inhibitors. A kinase inhibitor blocks the action of protein kinases, which add a phosphate group to a protein in a process called phosphorylation. Phosphorylation can turn a protein on or off, affecting its level of activity and function, and is often a required step in the growth of some cancers.
“This suggests these enzymes may hold the key to finding treatments that can help curb the spread of melanoma,” said Dajiang Guo, lead author of the study.
Of the identified kinase inhibitors, the researchers chose to test the effectiveness of the ataxia-telangiectasia mutated (ATM) inhibitor in the lab. They used CRISPR gene-editing technology to knock out the gene responsible for expressing ATM kinase in melanoma cells and found that the cells became less invasive and didn’t spread to the lymph nodes in mice as much.
“We believe that ATM may serve as a potent therapeutic target for treating the spread of melanoma in patients,” said Tikoo.
The study is a significant step forward in the fight against melanoma, the researchers say, laying the groundwork for future studies and the development of novel treatments.
“The combination of ‘Invasion-Block’ and ‘S-MARVEL’ is opening new avenues in the search for drugs that can arrest the spread of cancer,” Tikoo said.
The study was published in the journal PNAS.
Source: Centenary Institute