Targeting mitotic-exit phosphatases for cancer therapy.

Cell proliferation has long been recognized as a suitable target for chemotherapy. Despite their remarkable efficacy, the anti-mitotic agents that are currently used clinically cause severe side effects on healthy cells. Drugs that are more selective for cancer cells are therefore in great need. We propose to develop a novel, non-exclusive cancer therapy that aims at the inhibition of specific protein phosphatases that are essential for mitotic exit in cancer cells. The goal is to force a mitotic arrest in cancer cells so to trigger their death in mitosis. First, we will identify and characterize phosphatases that are rate-limiting for time-ordered steps of mitotic exit. Second, we will examine how the expression, activity and targeting of rate-limiting mitotic-exit phosphatases are altered during tumorigenesis and metastasis. Third, we will set up biochemical and cellular screens of small-molecule libraries for compounds that interfere with the functions of these key mitotic-exit phosphatases. The efficacy of these compounds in killing cancer cells will be tested in cellular and pre-clinical models.

Keywords:Tumor suppressors, Oncogenes, Proliferation, Mitosis, Protein phosphatases, Protein phosphorylation, Cancer therapy

Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences