We accept applications for the Pediatric Hematology/Oncology Fellowship Program at Penn State Children’s Hospital through the Electronic Residency Application Service (ERAS).
Learn about current basic science research opportunities in the in Division of Pediatric Hematology/Oncology in each of the physician laboratories listed below.
Laboratory of Barbara A. Miller, MD
The laboratory of Barbara A. Miller, MD, Chief of the Division of Pediatric Hematology/Oncology, focuses on the role of ion channels in cell proliferation, cell differentiation and regulation of bioenergetics. Dr. Miller's laboratory is studying the function of members of the TRP superfamily of ion channels in malignant cell proliferation with a focus in leukemia and neuroblastoma.
Members of this channel family typically have a high aberrant expression in many cancers and may contribute to the development of the malignant phenotype and chemotherapy resistance. Research focuses on the channel TRPM2, which is activated by oxidative stress, TNF-alpha and amyloid, and modulates cell survival and apoptosis through regulation of mitochondrial function and ROS. Because these channels are located on the cell surface, they have tremendous potential as future targets for drug therapy.
In work funded by the National Institutes of Health (NIH), Hyundai Hope on Wheels and St. Baldrick’s, Dr. Miller’s laboratory is exploring the role of these channels in malignant cell growth and as novel therapeutic targets.
Laboratory of Sinisa Dovat, MD, PhD
In the laboratory of Sinisa Dovat, MD, PhD, the long-term goal is to understand how gene dysregulation leads to malignant transformation in humans. The most important difference between cancer cells as compared to normal cells is in their way to divide and multiply. Cancer cells are immortal. They divide rapidly and they divide indefinitely. Normal cells multiply at a determined rate, and after certain number of divisions, they die.
In cancer cells, the mechanism which controls the life cycle of the cell is altered. The regulation of the life cycle of each cell is controlled by a set of specific genes. The focus of Dr. Dovat’s research is to discover how these genes control cellular fate.
The lab is focused on three research projects:
- To define the mechanism by which Ikaros protein suppresses the development of childhood leukemia. Absence of Ikaros’ function leads to development of childhood leukemia, and is a negative prognostic marker for this disease. Defining the mechanism by which Ikaros controls growth of leukemia cells will help to design a novel, targeted therapy.
- To elucidate epigenomic changes that control cellular immortalization and senescence. Results from the Dovat lab suggest that epigenomic changes in cells determine whether they divide indefinitely (become immortal) or completely stop dividing (become senescent). His lab is trying to dissect epigenomic events control cellular senescence in order to design a new class of drugs that regulate this process.
- To use functional genomics and system biology approach to accelerate discovery of new drugs and drug combinations for childhood malignancies. Dr. Dovat’s lab is using a novel approach to define the molecular mechanisms of how various drugs affect malignant cells. Results will help to define a rationale mechanism-based novel chemotherapeutic treatment for childhood cancer.
Research in the Dovat lab is patient-oriented and translational, with an emphasis on understanding basic mechanisms of disease in order to help in the design of more effective therapeutic strategies and agents. The goal is to provide cutting-edge therapies that integrate the latest research discoveries into clinical practice.
Laboratory of Wei Li, PhD
Research in the laboratory of Wei Li, PhD is interested in studying intercellular interactions during tissue homeostasis and determining how de-regulated interactions among cells promote cell transformation and tumor progression in brain cancer. The goal of his research is to find molecular targets and biomarkers for cancer therapy.
Dr. Li’s lab integrates molecular, cellular and biochemical approaches in combination with mouse tumorigenesis models. Currently, one of his major focuses is elucidating the regulation and function of the Hippo tumor suppressor pathway in brain tumors. In addition, his lab is using in vitro and in vivo models to dissect biological interactions between heterogeneous malignant cells and to study functional consequences of intra-tumor heterogeneity. He is also using functional screens, including genetic screens and small molecular screens, to search for oncogenic genes that can promote brain tumor growth.
Laboratory of Vladimir Spiegelman, MD, PhD
The laboratory of Vladimir Spiegelman, MD, PhD is focused on the understanding of molecular pathways and environmental factors that lead to development of human malignancies, and employment of newly acquired knowledge for eradication of cancer.
Dr. Spiegelman’s research focuses on the mechanisms that govern the turnover of short-lived mRNAs that encode important regulators of cell proliferation, death and differentiation, as well as the implications of this turnover for tumor development. The mechanisms regulating mRNA degradation, its alterations in human cancers and its potential ability of therapeutic modality are of primary interest.
In the series of recent manuscripts published in Nature (2006), Oncogene (2008), Molecular Cell (2009), Cancer Research (2009), Genes and Cancer (2010), Journal of Cell Science (2012), J. Biol. Chem. (2015) and others, Dr. Spiegelman’s group established the role and mechanism of RNA-binding protein CRD-BP in the regulation of expression of several important regulators of tumorigenesis, including ßTrCP1, c-myc, Gli1, and MITF.
CRD-BP is a novel transcriptional target gene of Wnt/ß-catenin/Tcf and c-myc. CRD-BP protein is essential for induction of mRNA of ßTrCP1, c-myc, Gli1, and MITF by ß-catenin signaling in several human cancers. Furthermore, high levels of CRD-BP that are found in primary tumors exhibiting active ß-catenin/Tcf signaling implicates CRD-BP induction in up-regulation of ßTrCP1, activation of NF-¿B suppression of apoptosis and resistance to chemotherapeutic agents in these diseases.
Dr Spiegelman’s lab continues to analyze the role that CRD-BP plays in the pathogenesis of variety of malignancies using in vitro and in vivo models, and also aim to identify novel mRNA targets of CRD-BP that are important for tumor progression, and look for the potential therapeutic ways of inhibiting the function of CRD-BP.
Laboratory of Hong-Gang Wang, PhD
The laboratory of Hong-Gang Wang, PhD, 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 his research team.
The body of his scientific work, encompassing a total of 135 articles, has been cited over 25,000 times with an h-index of 62. This laboratory has been continuously funded by the National Institutes of Health (NIH) since 1999 and provides an excellent training environment for students and fellows who are interested in basic and translational cancer research.
Three major research projects are currently underway:
- Study of 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. Dr. Wang’s group 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.
- Study of 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, Dr. Wang’s 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, his 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.
- Anticancer drug discovery and development. Dr. Wang’s laboratory has over 15 years’ experience in the development and characterization of selective inhibitors for anti-apoptotic Bcl-2 family proteins as anticancer drugs. His 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. His 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. Shantu Amin, his 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.
If you have questions, please contact:
- Anita Smith, pediatric fellowship program coordinator, at 717-531-0003, extension 287226, or firstname.lastname@example.org
- Anne English, Administrative Associate at 717-531-1789, or email@example.com.