Epithelial-Mesenchymal Transition in the Crosshairs: Novel Treatments to Kill Drug Resistant, Metastatic Cells in Cancer

Across many cancers, mortality is associated with metastasis and acquired drug resistance, both of which often manifest in recurrent disease. Central to these phenomena is epithelial to mesenchymal transition (EMT), a developmental process reactivated during tumor progression. During EMT, transcriptional regulation of cell adhesion and cytoskeletal genes is altered, and cells become motile. For many years, EMT has been closely tied to metastasis, but in recent years its roles in drug resistance and stem cell phenotype have also been uncovered. While EMT is thus an attractive therapeutic target, progress in drug development for EMT has been limited, as the transcription factors that mediate the process have been dubbed “undruggable”. Novel approaches are therefore needed.

Our recent work in ovarian cancer has revealed that mesenchymal cells may be vulnerable to therapies targeting DNA repair and VEGF signaling, but in unexpected ways. We present here our ongoing work exploring the use of olaparib, cediranib, and various marine alkaloids as a supplement to conventional chemotherapy to more effectively kill cancer cells, particularly those that have undergone EMT. We also present our comprehensive research paradigm, where we use live cell imaging in conjunction with drug screening and gene expression assays to paint a complete picture of EMT biomarkers, cell migration, and drug action across ovarian, colorectal, and oral cancers.

Learning Objectives: 

1. Describe the various effects of EMT in the course of cancer progression.

2. Explain the known and putative mechanisms of action of olaparib and cediranib.

3. Propose experimental designs involving complementary assay techniques.