Investigating programmed cell death in cancer biology
Programmed cell death plays a central role in normal biology and cancer pathogenesis. Our laboratory uses structural and chemical biology to explore the mechanisms underlying cell death. We are interested in identifying and understanding how programmed cell death pathways can be targeted as a therapeutic approach.
The mechanisms that manipulate programmed cell death play critical roles in regulating homeostasis but are often deregulated in cancer, which leads to chemotherapy resistance. Our research encompasses elucidation of the regulatory mechanisms responsible for apoptosis initiation and necroptosis execution, both of which involve membrane permeabilization events.
One of the main projects in our laboratory centers on mitochondrial poration, a point-of-no-return event in apoptosis that is regulated by BCL-2 proteins. The process is executed by the effector molecules BAK, BAX, and BOX, which form pores in the outer mitchondrial membrane to release proteins that activate the dismantling caspase cascade. How this poration occurs is poorly understood, despite the fact that the majority of drugs that induce apoptosis work by triggering this process. Using a multi-pronged structure-function approach, we are working to determine the individual steps in this mechanism.
Prosurvival BCL-2 proteins, the brakes on mitochondrial poration, are sought-after drug targets in cancer. The pharmaceutical industry has invested extensively in developing inhibitors of these proteins. One drug in particular, Venetoclax, has been approved by the FDA as a selective inhibitor of BCL-2 in several cancers, including chronic lymphoblastic leukemia and small lymphoblastsic leukemia. We are developing novel chemical probes against these proteins to validate the mechanism of poration by effectors and for use preclinically.
Necroptosis is a form of programmed necrosis regulated by receptor interacting protein kinase 3 (RIPK3) and the pseudokinase mixed lineage kinase domain-like (MLKL). We are elucidating the mechanism of activation of MLKL in necroptosis which involves phosphorylation by RIPK3 and binding induced triggering by several inositol phosphate metabolites. MLKL is thought to undergo major changes in conformation as it transitions from a dormant, soluble, monomeric form to a membrane associated oligomer that interacts with phospholipids to permeabilize the plasma membrane. We do not currently understand how active MLKL permeabilizes membranes.
Rational manipulation of necroptosis in cancer biology is still in its infancy. Accumulating evidence suggests the necroptosis is induced by cancer-targeting chemotherapeutics including DNA damaging agents. We seek to discover and design chemical probes that can modulate necroptosis by directly targeting the proteins involved in this pathway. Our laboratory has access to state-of-the-art compound libraries containing 600,000 compounds and screening facilities in the Department of Chemical Biology & Therapeutics, and we have developed robust platforms to discover chemical probes for any target of interest. We rationally design these lead compounds to act selectively in preclinical studies.
The research in our laboratory pushes the boundaries of structural biology as we strive to understand how things work at the membrane level. Our work involves a variety of techniques and methodologies, including cryo-EM, NMR, crystallography, as well as robust collaborations with colleagues in Protein Technologies Center, Single-Molecule Imaging Center, and Chemistry Centers.
Dr. Tudor Moldoveanu was formally trained as a biochemist and structural biologist at Queen’s University and McGill University in Canada before moving to St. Jude to expand his expertise in cell death programs. His path has equipped him with a unique set of skills, positioning him to ask some of the most challenging questions in his field. Dr. Moldoveanu is committed to expanding the reach of the institution, and engaging the next generation of scientists.
Committed team of scientists with an interest in asking challenging, creative questions related to cell death and disease