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MicroRNA Study Yields Potential Marker for Oligometastases Treatment Success

NEW YORK (GenomeWeb News) – The expression of microRNAs in the miR-200 family is elevated in oligometastases cases that fail to respond to aggressive treatment, according to a study appearing online last night in PLoS ONE, suggesting miRNA markers may help guide treatment for individuals with this type of metastasis.

While a subset of patients benefit greatly from targeted surgical or high-dose radiation treatments for oligometastases — metastatic tumors that are found at a limited number of sites but have not yet become widespread — others do not, authors of the new study explained. In their search for molecular clues as to why this is the case, the team, which included investigators from the University of Chicago and Duke University, assessed and compared miRNA levels in tumor samples from cancer patients who had received high-dose radiation therapy for oligometastases.

They found that those who went on to have more widespread tumor metastasis following targeted radiation treatment tended to have tumors with higher levels of miR-200 family miRNAs, particularly miR-200c, while those with lower levels of these miRNAs in their tumors responded better to the treatment.

"This finding means we can have a pretty good sense in advance of which patients we can help," co-corresponding author Ralph Weichselbaum, a University of Chicago researcher and director of the university's Ludwig Center for Metastasis Research, said in a statement. "Patients unlikely to benefit from focused, local therapy can move on to systemic treatment."

In previous studies, Weichselbaum and his colleagues reported that targeted high-dose radiation treatment could curb cancer progression in around one-fifth of cancer patients with five or fewer distant metastases under a certain size threshold.

For the current study, they focused on miRNA patterns in primary and/or metastatic tumors isolated from some patients treated in earlier studies, using Taqman real-time quantitative PCR to determine the expression of 376 miRNAs in 42 formalin-fixed, paraffin embedded tumor samples from individuals who did or did not respond to the targeted radiation treatment.

The researchers initially found 29 candidate miRNAs whose expression in the metastatic tumor samples apparently coincided with cancer progression. Another 17 miRNAs were selected for further study based on their expression patterns in the primary tumors tested.

Follow-up analyses on these miRNA sets indicated that a miR-200 family miRNA called miR-200c was among the most promising potential markers for targeted treatment outcome, since its expression corresponded to poor oligometastases response to targeted radiation as well as metastatic characteristics in cell line and animal model experiments.

For instance, researchers found that the number of distant metastases increased in mouse models of cancer that were transfected with miR-200c. Their initial follow-up work indicated that this metastatic action may be a consequence of lower-than-usual levels of some genes regulated by miR-200c, such as the TGF-beta and Rho signaling-related genes NEDD4L and FGD1.

Although more studies of miR-200c and other miRNAs that may herald oligometastases progression are needed, those involved in the study are optimistic that such molecular markers — combined with information on the clinical features of metastatic tumors — could eventually make it more straightforward to settle on a treatment strategy for individuals with a limited number of metastatic tumors.

"Our findings are an initial step in discriminating between patients with a few treatable sites where the tumor has spread and those who will develop widespread metastasis, which is not curable with focused radiation therapy," Weichselbaum said. "It is encouraging to find a common molecular basis for this treatable state across a broad variety of metastases from solid tumors."

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