Targeted Therapy Identified for Protein That Protects and Nourishes Cancer

Newswise HOUSTON Scientists at The University of Texas MD Anderson who identified a proteins dual role in cancer promotion have discovered a way to shut it down, opening a potential new avenue for cancer treatment.

Reporting this week in the journal Cell, the researchers describe the first compound that directly binds to and blocks Skp2, a protein they previously showed both turns off a cellular defense against cancer and switches on a cancer-feeding metabolic pathway.

The beauty of this study is we identified an inhibitor and showed how it functions to block Skp2. Inhibitors often are discovered without an initial understanding of how they work, said co-senior author Hui-Kuan Lin, Ph.D., associate professor of Cellular and Molecular Oncology at MD Anderson.

Lin teamed with co-senior author Shuxing Zhang, Ph.D., assistant professor of Experimental Therapeutics and head of the Integrated Molecular Discovery Laboratory at MD Anderson, to identify and characterize the drug.

There are many more chemical compounds available than there are estimated stars in the universe, Zhang said. We have a database with 10 million compounds, but our prescreening analysis narrowed our computerized search to 120,000 and then further to find small-molecule candidates that inhibit Skp2.

Their inhibitor plugs critical binding sites on Skp2, preventing it from connecting to Skp1 to form a complex, which is the first step in its two cancer-promoting functions, Lin said.

Compound hits prostate, lung tumors

This compound has a high degree of specificity our tests in prostate and lung cancer show it preferentially targets the cancer cells but not the normal cells, Lin said. Steps remain to define the drugs potential off-target effects before it can advance to human clinical trials, Lin said.

The researchers also found that the inhibitor suppresses prostate cancer stem cells, which play a role in cancer initiation, progression and resistance to chemotherapy.

Normally, Skp2 E3 ligase binds to and tags other proteins with molecules called ubiquitins, which can serve as activation signals or as targets marking the protein for destruction. Skp2 is overexpressed in numerous cancers and plays a critical role in cell cycle progression leading to cell division, metabolism and dormancy, as well as cancer progression and metastasis.

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Targeted Therapy Identified for Protein That Protects and Nourishes Cancer