Cancer Stem Cells & Necroptosis
Ilana Chefetz, Ph.D.
Our lab studies the molecular and metabolic aspects of cell programmed necrosis (necroptosis) in order to design targeted therapies and prevent recurrent disease. Cell programmed necrosis or necroptosis is a recently identified novel regulated cell death pathway. Cell death with necrotic morphology and features is thought to be a non-regulated and uncontrollable event associated with cell injury, inflammation or ischemia. However, recent studies now reveal that necrosis can occur in regulated manner. Necroptosis participates in pathogenies of diseases including neurodegeneration, ischemia and heart disorders, and viral infections; thus targeting necroptosis will prevent or mitigate undesirable cell death. On the other hand, drugs, inducing necroptotic cell death in tumors, can potentially overcome drug resistance in cancer cells due to elevated expression of anti-apoptotic proteins. Thus, elucidation of necroptosis/cell proliferation or necroptosis/apoptosis balance is essential to trigger cancer cell death or prevent pathological conditions such as ischemia or inflammation. The most studied kind of necroptosis is initiated by TNF-α while Caspases are inhibited using pan-Caspase inhibitor ZVAD-FMK. This requires the kinase activity of receptor-interacting proteins 1 and 3 (RIPK1 and RIPK3) to follow their downstream target MLKL. Necroptosis execution involves formation of micro-complex (20 MDa) necroptosome followed by disintegration of mitochondrial and plasma membranes. Despite necroptosis importance, many molecular downstream events are unknown or being disputed.
Current research projects:
- Novel combination therapy in high grade serous ovarian cancer- dual inhibition of ALDH1A and MEK1/2
- Novel compounds that target Oxidative Phosphorylation as a preferable source of energy of ovarian cancer stem cells
- Effect of exosomes on ovarian cancer cell, purification and characterization
- A Novel Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-Like cells. September 21st, 2017. Mayo Clinic, Ovarian cancer spore group
- A Novel Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-Like cells. June, 2018. University of Chicago, OBGYN department