New potential drug target for cancer identified

Washington, February 14 (ANI): Scientists have identified a pivotal protein in a cellular transformation that makes a cancer cell more resistant to treatment and more capable of growing and spreading, making it an inviting new target for drug development.

Additionally, the international team led by scientists at The University of Texas MD Anderson Cancer Center found the cancer drug sunitinib potentially has a new role in treating triple-negative, claudin-low breast cancer, a particularly resistant version of a type of cancer that is already difficult to treat.

"We found that FOXC2 lies at the crossroads of the cellular properties of cancer stem cells and cells that have undergone epithelial to mesenchymal transition (EMT), a process of cellular change associated with generating cancer stem cells," said senior author Sendurai Mani, Ph.D., assistant professor in MD Anderson's Department of Translational Molecular Pathology and co-director of the Metastasis Research Center.

Cancer stem cells are fewer in number than other tumor cells, yet research has tied them to cancer progression and resistance to treatment. Abnormal activation of the epithelial to mesenchymal transition can create cancer stem cells, Mani noted.

"There are multiple molecular pathways that activate EMT. We found many of these pathways also activate FOXC2 expression to launch this transition, making FOXC2 a potentially efficient check point to block EMT from occurring," Mani said.

Research uncovering this connection focused on cell line and mouse model experiments. The next important step will be to assess the expression and activity of FOXC2 in human tumor samples, he said.

In the meantime, sunitinib, known commercially as Sutent and approved by the U.S. Food and Drug Administration for three other cancers, provides interesting, more immediate, potential.

"FOXC2 is a transcription factor, a protein that binds to DNA in the promoter region of genes to activate them. For a variety of reasons, transcription factors are hard to target with drugs," Mani said.

The team found that FOXC2 also regulates the platelet derived growth factor receptor (PDGFR-Beta). In cancer cell lines, they found that the PDGFR-Beta inhibitor sunitinib inhibited growth of cells with EMT or cancer stem cell properties that have active FOXC2.

Mice with triple-negative breast cancer treated with sunitinib had smaller primary tumors, longer survival, and fewer incidences of metastasis. There also was a steep drop in the cells' ability to form mammospheres, a hallmark of cancer stem cells.

Mani said the team believes that targeting FOXC2 pathway using either PDGFR-beta inhibitors or other yet-to-be-known small-molecule inhibitors will be an effective therapeutic strategy for inhibiting EMT and consequently reducing EMT/cancer stem cell-associated metastasis, relapse and therapy resistance.

The study has been published in the journal Cancer Research. (ANI)

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