Cancer treatments often fail because cancer cells develop resistance to chemotherapy drugs and the invasive characteristics of cancer tumor cells increase in response to chemotherapeutic processes. Currently, treatments to suppress metastasis involve high does of individual drugs or combinations of drugs that target pathways that promote the spread of cancer cells; however, these treatments are often not effective as they can activate other pathways that make the treatments less effective or stop them working altogether. High doses of drugs can also be toxic to healthy cells.
New methods of blocking metastasis are desperately needed, especially for aggressive and difficult to treat cancers such as triple-negative breast cancer.
A team of researchers at the University of Chicago, the University of São Paulo in Brazil, the University of North Carolina, and the University of Texas Southwestern Medical Center, have devised a new approach involving a low-dose combination of four drugs that has been shown to be effective at stopping metastasis in mice without triggering drug resistance. This is achieved by simultaneously targeting multiple pathways in a metastasis promoting network.
“Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation,” explained the researchers. “Here we show that targeting driver network signalling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy.”
An analysis was conducted of gene expression data from patients participating in the Cancer Genome Atlas study to investigate how the metastasis-suppressing protein Raf Kinase Inhibitory Protein (RKIP) works. “[RKIP] moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastatic BACH1 and motility-related target genes,” explained the researchers.
The researchers developed a four-drug combination therapy that replicated how RKIP supresses metastasis and found that it blocked metastatic colonization in mouse breast cancer models and increased survival.
Computer modelling was then used to determine why reducing the expression of the network of genes involved in the prevention of metastasis was more effective than stopping their activity altogether, and how this helped to prevent drug resistance or relapse.
“Our findings could lead to a new cancer treatment strategy where patients first receive low-dose combination drugs that block metastasis and then receive traditional cancer treatments such as radiation, chemotherapy, or immunotherapy,” said Marsha Rosner, co-senior author and the Charles B. Huggins professor at the Ben May department of cancer research at the University of Chicago.
You can read more about the study in the paper – Limited inhibition of multiple nodes in a driver network blocks metastasis – which was recently published in the journal eLife. DOI: 10.7554/eLife.59696