|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 aims to better understand the mechanisms by which tumor cells escape from cell death, a hallmark of cancer. Specifically, this group researches the interplay of autophagy (self-eating) and apoptosis (self-killing) in the context of oncogenesis and chemotherapy. Apoptosis is an extensively studied mechanism of programmed cell death that is characterized by caspase activation, whereas autophagy is a cellular waste management system that is activated to maintain cellular homeostasis. In addition, targeting of these two closely related but distinct self-destructive processes for anticancer drug discovery and development is another major interest of the research group. This laboratory has been continuously funded by the NIH since 1999 and provides an excellent training environment for students and fellows who are interested in basic and translational cancer research. The ultimate goal of our research is to translate basic science discoveries to the development of new approaches for the treatment and prevention of cancer. Three major research projects are currently underway:
1. The Molecular Machinery of Autophagy: Autophagy is an evolutionarily conserved lysosomal catabolic pathway that plays essential roles in intracellular quality control, cell survival, immunity, and tissue homeostasis. Despite advances in understanding the molecular mechanisms of autophagy, the origin of autophagosomal membranes and the mechanisms of membrane expansion and closure remain largely uncharacterized. Our research has shown that BIF-1, a member of the membrane curvature-driving endophilin family, interacts with the class III phosphatidylinositol 3-kinase (PIK3C3) complex II (PIK3R4-PIK3C3-BECN1-UVRAG) through UVRAG to mediate Golgi fission and generate Atg9-positive Golgi-derived vesicles (A9+GDVs) during autophagy. Furthermore, loss of BIF-1 under metabolic stress results in an accumulation of endoplasmic reticulum (ER)-associated unclosed autophagosomal structures, suggesting that A9+GDVs may play a key role in the completion of autophagosome formation. Currently, the precise mechanisms underlying the generation of BIF-1-dependent A9+GDVs and the closure of autophagosome are under investigation.
2. The Functional Significance of Autophagy in Cancer Development and Treatment: Autophagy a double-edged sword in cancer as it can either suppress cancer initiation by limiting oxidative stress, chronic inflammation, and genome instability or promote cancer cell survival by maintaining cellular nutrient, energy, and organelle homeostasis. The paradoxical functions of autophagy present a challenge when attempting to determine the appropriate modulation of autophagy for cancer therapy. While apoptosis and autophagy utilize fundamentally distinct machinery, the two pathways are highly interconnected and share many key regulators. Notably, our research has recently demonstrated that the autophagosomal membrane serves as a site of caspase-8 activation through an intracellular death-inducing signaling complex (iDISC), indicating that autophagy can also function to induce apoptosis. Several lines of research are underway to induce iDISC assembly as a novel approach to switch pro-tumorigenic autophagy to caspase-8-dependent apoptosis to limit malignant progression and enhance the efficacy of anticancer therapies. In addition, this laboratory is actively investigating the role of intratumor autophagy heterogeneity in cancer metastasis and the effects of autophagy deficiency in bone marrow niche cells on hematopoiesis and leukemogenesis.
3. Anticancer Drug Discovery and Development: This laboratory has over 15 years experience in the development and characterization of selective inhibitors for anti-apoptotic Bcl-2 family proteins as anticancer drugs. My work with Dr. Andy Hamilton was the first to rationally design a series of Bcl-2 antagonists based on a terephthalamide or terphenyl scaffold to mimic the alpha-helical region of the Bak BH3 peptide. Our 2012 report with Dr. Qing Lin at SUNY Buffalo presents a nice example of structure-based design and chemical synthesis of stapled peptide inhibitors of the BH3-Mcl-1 interaction that have potential utility in cancer therapy. In collaboration with Dr. Rongshi Li and Dr. Shantu Amin, this group has recently identified the natural product marinopyrrole A (maritoclax) and its derivatives as a novel class of Mcl-1 inhibitors that antagonize Mcl-1 and overcome multidrug resistance in hematological malignancies by targeting Mcl-1 for proteasomal degradation. Currently, efforts are underway to improve the potency and selectivity of maritoclax and to identify and develop autophagy inhibitors as cancer therapeutics.
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