Low-dose, four-drug combo blocks cancer's spread in mice

Bottle of pills

New research out of the University of Chicago shows that low doses of a four-drug combination help prevent the spread of cancer in mice without triggering drug resistance or recurrence. The research was published on May 11 in eLife.

The findings suggest a new approach to preventing cancer metastasis in patients by simultaneously targeting multiple pathways within a metastasis-promoting network. They may also help identify people who would most likely benefit from such treatment.

Metastasis, the spread of cancerous cells through the body, is a common cause of cancer-related deaths. Current approaches to treating metastatic cancer have focused on high doses of individual drugs or drug combinations to hinder pathways that promote the spread of cancer cells. But these approaches can be toxic to the patient, and may inadvertently activate other pathways that cause the drugs to stop working and the tumors to return.

“There is an urgent need for new strategies to suppress cancer metastasis, especially for cancers such as triple-negative breast cancer that currently lack effective therapies,” says first author Ali Yesilkanal, PhD, a postdoctoral scholar at the Cancer Genome Atlas study to understand how a metastasis-suppressing protein called Raf Kinase Inhibitory Protein (RKIP) works. They found that RKIP reduces the expression of a network of genes that promote the spread of cancer cells.

They then created a four-drug combination that mimics how RKIP suppresses the ability of cancer cells to spread. They administered low doses of this treatment to mouse models of metastatic breast cancer, and found that it blocked the spread of cancer and increased the animals’ survival. Importantly, the treatment did not trigger the compensatory mechanisms that often cause high-dose, anti-metastasis drugs to stop working and tumors to return.

Finally, the team used computer modeling to explain why reducing, but not completely stopping, the expression of this network of genes helped prevent metastasis without triggering drug resistance or relapse. They also identified patients with breast cancer in the Cancer Genome Atlas who might be most likely to benefit from such treatment based on their cancer’s gene expression patterns.

“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,” says co-senior author Marsha Rosner, PhD, the Charles B. Huggins Professor at the Ben May Department for Cancer Research at UChicago.

“Our results challenge current approaches to cancer treatment and suggest an alternative strategy for controlling metastasis in breast cancer and potentially other types of cancer,” concludes co-senior author Alexandre Ramos, PhD, Group Leader at the School of Arts, Sciences and Humanities, University of São Paulo, Brazil.

The study, “Limited inhibition of multiple nodes in a driver network blocks metastasis,” was supported by the National Institutes of Health (R01-GM121735-01 and CA058223). Additional authors include Dongbo Yang, Andrea Valdespino, Payal Tiwari, Long Chi Nguyen, Jiyoung Lee, Xiao-He Xie, Siqi Sun, Christopher Dann, Lydia Robinson-Mailman, Ethan Steinberg, and Casey Frankenberger of UChicago; Alan U Sabino of the University of São Paulo; Timothy Stuhlmiller and Gary L Johnson of the University of North Carolina at Chapel Hill; and Elizabeth Goldsmith of the University of Texas Southwestern Medical Center.

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