|Institution||College of Medicine|
|Address||500 University Drive Hershey PA 17033|
Lois High Berstler Professor, Pediatrics and Pharmacology
Director, Pediatric Molecular Oncology Program
SECONDARY APPOINTMENT(S)/ INSTITUTE(S)/ CENTER(S):
Pharmacology, Penn State Hershey Children’s Hospital, Penn State Hershey Cancer Institute, The Huck Institutes of the Life Sciences
GRADUATE PROGRAM AFFILIATIONS:
Cell and Molecular Biology, Pharmacology, Biomedical Sciences: Translation Therapeutics Option, Integrative Biosciences: Molecular Medicine
B.S., University of Tsukuba, 1987
Ph.D., University of Tsukuba, 1992
Postdoctoral Training, Burnham Institute, 1993-1998
Research in this laboratory is concerned with understanding the fundamental mechanisms that control apoptosis (self-killing) and autophagy (self-eating) in the context of tumorigenesis and drug resistance. In addition, targeting of these two closely related but distinct cellular processes for anticancer drug discovery and development is another major interest of our research group. We discovered a novel tumor suppressor, Bif-1, that activates not only apoptosis but also autophagy. Bif-1 is involved in the conformational activation of Bax, a key pro-apoptotic Bcl-2 family member, at the mitochondria during apoptosis. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagosome formation and Atg9 trafficking through mediation of Golgi fragmentation during nutrient starvation. Importantly, the expression of Bif-1 is lost or decreased in various human cancers, and the deletion of Bif-1 promotes tumor development in mouse models. We were among the first to physically link AMPK, a cellular energy sensor, to ULK1, a key initiator of autophagy, in the regulation of mammalian autophagy. Our work suggests that the formation of an intracellular death-inducing signaling complex (iDISC) on the autophagosomal membrane can switch autophagy from pro-survival to pro-apoptotic signaling. In addition, our group has recently identified the natural product marinopyrrole A as a novel small molecule Mcl-1 inhibitor, maritoclax, which antagonizes Mcl-1 by targeting Mcl-1 for proteasomal degradation in a manner that functionally mimics Noxa binding to Mcl-1. This unique mechanism of action is in sharp contrast to canonical BH3 mimetics that exert their inhibitory function through disruption of pro- and anti-apoptotic Bcl-2 family protein complexes. Maritoclax is effective as a single agent against human leukemia cells with elevated Mcl-1 expression, sensitizes multidrug resistant AML cells to the Bcl-2 inhibitor ABT-737 and overcomes Mcl-1-mediated resistance to apoptosis. The ultimate goal of our research group is to translate basic science research discoveries to the development of new approaches for the treatment and prevention of cancer.
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