Editor’s note: this is the first in a series of posts highlighting drug screening studies in our Conrad Prebys Center for Chemical Genomics. Read the second post here.
To metastasize, some types of cancer cells rely on invadopodia, cellular membrane projections that help them “walk” away from the primary tumor. To determine how cells control invadopodia formation, scientists at Sanford-Burnham took advantage of the technology and expertise of the Institute’s Conrad Prebys Center for Chemical Genomics to screen a collection of pharmacologically active compounds to identify those that either promote or inhibit the process.
The study identified several compounds that block invadopodia and found that many of the compounds targeted Cdks, a family of enzymes that were not previously associated with invadopodia. One of these enzymes, Cdk5, is required for the formation and function of invadopodia and for cellular invasion.
The research team also worked out how Cdk5 promotes invadopodia formation: Cdk5’s action leads to the degradation of another protein, caldesmon, which was previously shown to negatively regulate invadopodia, explaining why the Cdk inhibitors identified in the screening study also inhibited invadopodia.
Another pharmacologically active compound shown by the screen to regulate invadopodia was paclitaxel, a drug used to treat patients with many forms of cancer. Paclitaxel’s antitumor activity is based on its ability to bind and stabilize microtubules, one component of the cellular cytoskeleton, thereby halting cell division and inducing cellular suicide. In the study, paclitaxel promoted invadopodia formation and cancer cell invasion.
The results raise the concern that continued treatment with paclitaxel might be counterproductive in cancer patients who aren’t responding well to the drug or in cases where the tumor has not yet been removed.
The study was led by Sara Courtneidge, Ph.D., director of the Tumor Microenvironment Program in Sanford-Burnham’s NCI-designated Cancer Center, and postdoctoral researcher Manuela Quintavalle, Ph.D., in collaboration with scientists in the Conrad Prebys Center for Chemical Genomics.