Faculty
Program Faculty members serve as mentors for trainees seeking experience in basic cancer research. The faculty members are listed below, along with their primary department/institute affiliation and a brief description of their cancer-related research activities.
Cory Abate-Shen, Ph.D. (Urology) - Modeling Cancer in Mutant Mice
A major research interest of this laboratory is understanding the relationship between normal development and cancer using mouse models to investigate these processes. A major area of interest is prostate cancer as well as bladder cancer. Dr. Abate-Shen has developed mouse models that recapitulate the various stages of prostate cancer, which they are using to investigate the molecular mechanisms of disease progression as well as in preclinical studies for the development of novel therapeutics. Dr. Abate-Shen has a particular interest in using mouse models for the development of novel therapeutic and chemopreventive approaches for cancer.
Back to top
Richard Baer, Ph.D. (ICG) - The BRCA1 Tumor Suppressor Pathway in Hereditary Breast and Ovarian Cancer
The aim of the laboratory is to elucidate the biological functions of BRCA1 and determine why loss of these functions predisposes women to breast and ovarian cancer. These studies have led to the identification of two proteins that interact with BRCA1 in vivo: BARD1 and CtIP. The heterodimer formed by BRCA1 and BARD1 is a potent ubiquitin E3 ligase and appears to be the main physiological mediator of BRCA1 functions. Moreover, since mutations of the BARD1 gene are observed in breast, ovarian and endometrial carcinomas, BARD1 itself can also serve as a tumor suppressor. To gain further insights into the mechanism of BRCA1-mediated tumor suppression, the laboratory is studying the regulation of BRCA1/BARD1 enzymatic activity, identifying enzymatic substrates of BRCA1/BARD1, and evaluating the role of these substrates in the DNA damage response.
Back to top
Timothy Bestor, Ph.D. (Genetics & Development) - Epigenetic Regulation by DNA Methylation
Genomic methylation patterns are essential for genome stability, allele-specific expression of imprinted genes, X chromosome inactivation, and transcriptional repression of transposons. Global genome demethylation is lethal to differentiated cells, and focal de novo methylation or demethylation is involved in human cancer and a variety of developmental abnormalities. Methylation patterns are established and maintained by DNA (cytosine-5)-methyltransferases. The aim of this laboratory is to determine the biological functions of DNA methyltransferases in normal cells and how these functions are altered in human neoplastic diseases.
Back to top
Kathryn Calame, Ph.D. (Microbiology) - Regulatory Mechanisms of B Lymphocyte Development
The aims of this laboratory are to determine the mechanisms that control B lymphocyte development and how disruption of these mechanisms contributes to lymphoid neoplasia. A major focus is the analysis Blimp-1 (B lymphocyte induced maturation protein) an unusual transcriptional repressor that can drive B cells to differentiate into end-stage effectors of the B cell lineage called plasma cells. Thus, Blimp-1 has been described as a “master regulator” of terminal B cell differentiation. Another focus of the laboratory is the regulation of immunoglobulin gene rearrangement. While this process is essential for normal B cell development, aberrant immunoglobulin rearrangements are a major cause of proto-oncogene activation in human B cell tumors.
Back to top
Andrea Califano, Ph.D. (Biomedical Informatics) - Bioinformatics of Human Cancer
This laboratory studies cancer development at the interface of computational and experimental biological sciences. A bioinformatics tool, ARACHNE, has been developed for deconvolution of key cancer-related pathways in human tumor cells and has been successfully applied to decipher regulatory sub-networks involving the major proto-oncogenes implicated in human B cell lymphoma (c-Myc and BCL6). The laboratory is also working closely with the National Cancer Institute to develop caWorkbench, a Plug & Play platform for integrated genomics sponsored by the NCI caBIG project and the AMDeC foundation. This platform includes over 50 interoperable modules that allow the management, analysis, and visualization of a variety of biomedical data, including protein and DNA sequences, gene expression and genotypic data, pathways, genetic and clinical ontologies.
Back to top
Raphael Clynes, M.D., Ph.D. (Microbiology) - Fc Receptors in Tumor Immunity
The aim of this laboratory is to understand the immunobiology of Fc receptor function as it relates to tumor immunity. Fc receptors (FcRs) link the cellular and humoral response in both the sensitization and effector phases of the immune response. In the sensitization phase, FcRs function as antigen-uptake receptors on antigen presenting cells, including dendritic cells, while their expression on myeloid effector cells and NK cells mediate antibody-mediated effector inflammatory and cytotoxic responses. This laboratory has shown that immune complexes are potent inducers of both class I and class II-restricted immune response in vivo and can induce both tumor immunity and DTH responses. Currents efforts include identifying the FcR-bearing effector cell(s) responsible for both antibody-mediated tumor protection, investigating the regulatory roles of inhibitory and activating FcRs on dendritic cells and their contributions to anti-tumor antibody efficacy, and developing new approaches to target FcRs for vaccine delivery.
Back to top
Carlos Cordon-Cardo, M.D., Ph.D. (Pathology & Cell Biology) - Molecular Pathology in Oncology
This laboratory studies mechanisms of tumor suppression by characterizing tumor suppressor gene mutations in solid tumors, analyzing cell-cycle regulators, and developing faithful animal models of cancer. Two tumor types have been selected for hypothesis testing and experimental analysis: genitourinary carcinomas (including bladder and prostate tumors) and soft-tissue sarcomas. Research on bladder cancer is aimed at molecular characterization of the genes involved in the pathogenesis and multistep progression of uroepithelial neoplasms. Work from this laboratory has determined the clinical implications of detecting TP53 and RB alterations as they relate to disease progression and death due to bladder cancer. Based on these and other reported data, clinical protocols aimed at bladder preservation are being implemented. High throughput approaches using cDNA and oligonucleotide microarrays are also being utilized to further delineate molecular alterations associated with bladder cancer progression. Research dealing with prostate cancer has revealed the significance of the p27/KIP1 and the Pten/Akt pathways, among others, in prostate cancer progression. More recent data indicates that hormonal independence might be associated with mdm2 overexpression, affecting p53 stability, and increased cyclin D1 expression, affecting pRB phosphorylation.
Back to top
Franklin D. Costantini, Ph.D. (Genetics & Development) - Function of the RET Oncoprotein
Model systems are used to study mammalian embryogenesis and organogenesis and to explore the role of developmental factors in tumor formation. For example, the Ret proto-oncogene encodes a receptor tyrosine kinase with diverse roles in mammalian development and disease. Loss-of-function RET mutations are associated with Hirschsprung’s disease, which results from defects in the formation of the enteric nervous system from neural crest progenitors, while gain-of-function mutations can cause cancers including Multiple Endocrine Neoplasia. The laboratory is investigating how RET regulates the proliferation, migration, survival, and differentiation of neural crest cells using knock-in mouse models, as well as organ and cell culture systems. These studies should elucidate how malignantly activated RET promotes tumor formation and may also uncover downstream signaling pathways that might serve as targets for therapeutic intervention in RET-related cancers.
Back to top
Riccardo Dalla-Favera, M.D. (ICG) - Molecular Pathogenesis of Human Lymphoma
The goal of this laboratory is to identify the genetic lesions responsible for human B cell lymphomagenesis, to determine the mechanisms by which these lesions are engendered, and to elucidate the contribution of each lesion to tumor development. Specific lines of investigation include: 1) Elucidating the role of chromosomal translocations involving the c-Myc proto-oncogene in Burkitt's lymphoma and analyzing the biochemical mechanisms by which c-Myc controls normal and malignant cell proliferation. 2) Studying the normal and pathologic functions of BCL-6, a proto-oncogene that is malignantly activated in human lymphoma and encodes a transcription factor required for germinal center formation. 3) Exploring the mechanism of somatic hypermutation (SHM) during B cell development and the role of aberrant SHM as a source of genome instability during lymphoid neoplasia.
Back to top
Argiris Efstratiadis, M.D., Ph.D. (Genetics & Development) - Mouse Models of Human Cancer
Mammary tumor progression is investigated in mice using transgenic and gene targeting approaches, including a novel knock-in strategy for conditional, tissue-specific overexpression of oncoproteins. Specifically, tumor development is examined in compound mutant progeny derived from crosses between various genetically-modified mice that are tumor-prone because of overexpression of oncogenes or lack of tumor suppressors. A major focus is to examine oncogenic pathways implicated in human breast cancer, including activation of the c-Myc and ErbB2/neu genes and inactivation of the Brca1/2, p53, and PTEN tumor suppressors. In addition, the identification of new synergistic interactions between oncogenic pathways contributing to mammary tumor progression are being sought using an approach for insertional somatic mutagenesis with transposon tags.
Back to top
Adolfo Ferrando, M.D., Ph.D. (ICG) - Molecular Basis of Pediatric Leukemia
The aim of the laboratory is to determine the molecular mechanisms responsible for T cell acute lymphoblastic leukemia (T-ALL), an aggressive childhood malignancy. Two specific lines of investigation are currently underway. 1) The TAL1, HOX11 and HOX11L2 proto-oncogenes are each activated by chromosomal translocations in T-ALL. Since these genes encode DNA-binding transcription factors, the target genes regulated by these proteins are being defined by a combination of genomic technologies including gene expression profiling and chIP-on-chip analysis. The role of these genes in the proliferation and survival of leukemic cells will then be evaluated with a view toward the development of novel anti-leukemic drugs. 2) Dr. Ferrando and his colleagues recently observed that over 50% of T-ALL patients harbor tumor-specific mutations in NOTCH1 that cause oncogenic activation of this critical signaling molecule. Therefore, the laboratory is investigating the mechanisms by which these mutations promote leukemogenesis and exploring the use of known NOTCH1 inhibitory drugs as anti-leukemic agents.
Back to top
Jean Gautier, Ph.D. (ICG) - Genome Stability and the Cellular Response to DNA Damage
The frog Xenopus laevis is used as a simple model system to study processes that govern genome stability, including DNA replication control, cell cycle checkpoint regulation, and the cellular response to DNA damage. In addition, cultured mammalian cells and mouse models are exploited to analyze biological responses to DNA damage. Several specific questions are currently being addressed: 1) How is the ordered progression of the cell cycle maintained and how is DNA replication restricted to once per cell cycle 2) How is the cell cycle regulated following DNA damage and what are the biochemical roles of ATM in this process 3) What are the mechanisms that regulate exit from mitosis and chromosome segregation
Back to top
Edward P. Gelmann, M.D. (Medicine) - Molecular Genetics of Prostate Cancer
The laboratory works on NKX3.1, the gatekeeper suppressor protein that affects the initiation of most sporadic human prostate cancer. NKX3.1 is a multifunctional homeodomain protein with a broad range of interactions that affect cell signaling, DNA repair, and growth control. NKX3.1 expression is affected by genetic loss, by DNA methylation, and by protein degradation induced by chronic inflammation in the aging prostate gland. Inflammation-associated protein loss is mediated by phosphorylation of NKX3.1. One of the goals of the lab is to identify the kinases that phosphorylate NKX3.1. These kinases are targets for pharmacologic inhibition that may be applied to prostate cancer prevention or treatment.
Back to top
Stephen P. Goff, Ph.D. (Biochemistry & Molecular Biophysics) - Viral Oncology and Tyrosine Kinase Function
Two areas of viral oncology are currently pursued in this laboratory. Tumorigenesis in animals is studied through analysis of the replication cycle of Moloney murine leukemia virus, a prototypic retrovirus that induces transformation by proviral integration. Human neoplasia is under investigation through analysis of Hepatitis C, a causative agent of hepatocellular carcinoma and lymphoma. In addition, the laboratory is examining the functions of the c-Abl oncoprotein, a tyrosine kinase that is activated by chromosomal rearrangement in acute leukemia and has been implicated in the cellular response to oxidative stress.
Back to top
Maxwell E. Gottesman, M.D., Ph.D. (Biochemistry & Molecular Biophysics) - Control of Cell Growth and Differentiation
The laboratory is investigating the molecular mechanisms of cAMP signalling to understand how signal transduction pathways regulate cell growth, differentiation, and apoptosis. In particular, cAMP signal transduction and PKA anchoring are studied in purified cell-free systems and cultured cell lines to determine how cAMP signals are transduced to different parts of the eukaryotic cell. The laboratory also uses cycling Xenopus oocyte extracts as a model to dissect the role of cAMP in cell cycle progression.
Back to top
Wei Gu, Ph.D. (ICG) - Control of the p53 Tumor Suppressor Pathway
The p53 tumor suppressor is often described as the “guardian of the genome” because of its central role in coordinating cellular responses to DNA damage and other forms of cellular stress. In stressed cells, the p53 transcription factor is activated to induce anti-proliferative effects through mechanisms that include cell cycle arrest, apoptosis, and cellular senescence. The goal of the laboratory is to understand how the p53 mediates these anti-proliferative effects and how its activity is regulated. Biochemical and cellular approaches are used to define post-transcriptional modifications required for activation of p53 and to identify novel regulators and downstream effectors of p53 function. These novel components of the p53 pathway are also studied as potential targets for therapeutic intervention, and the genes encoding these components examined for tumorigenic lesions in human cancer.
Back to top
Antonio Iavarone, M.D. (ICG) - Cell Cycle and Differentiation in Tumors Derived from the Nervous System
The aim of the laboratory is to identify the molecular mechanisms by which anaplasia (loss of differentiation) and deregulated cell proliferation are linked in tumors derived from the nervous system. In the course of these studies, a protein network including the Rb tumor suppressor protein, the helix-loop-helix protein Id2, and the basic helix-loop-helix transcription factors was identified as a major determinant of normal brain development and shown to be deregulated in neuroectodermal tumors. Experiments are in progress to identify and characterize the multiprotein complexes engaged by this network and to determine how molecular alterations within this network promote brain tumor formation.
Back to top
Laura Johnston, Ph.D. (Genetics & Development) - Coordination of Growth and Cell Division
The laboratory studies how growth and cell division are coordinated during development to ensure that animals achieve the right size and shape. Experiments in both vertebrates and invertebrates have illustrated the competitive nature of growth and led to the idea that competition is a mechanism of regulating organ and tissue size. Work in this laboratory has shown that local expression of the Drosophila growth regulator dMyc, a homolog of the c-Myc proto-oncogene, induces cell competition and leads to the death of nearby wild-type cells in developing wings. Thus, dMyc-mediated cell competition may control organ size during normal development, and disruption of this process may be a key aspect of malignant development in tumors induced by Myc gene deregulation.
Back to top
Jessica Kandel, M.D. (Surgery) - Anti-angiogenic Therapy for Pediatric Tumors
The Pediatric Tumor Biology Laboratory, co-directed by Drs. Kandel and Yamashiro, focuses on the role of angiogenesis in promoting the growth and metastasis of pediatric solid tumors. To test the effect of blocking angiogenesis in these tumors, xenograft models of neuroblastoma, Wilm’s tumor, hepatoblastoma, and rhabdoid tumor of the kidney were developed. With these systems, the laboratory has shown that blocking vascular endothelial growth factor (VEGF) markedly suppresses the growth of microscopic tumors by inhibiting angiogenesis. The xenograph models are now being used to determine the mechanisms by which anti-angiogenic agents suppress tumor growth, and to identify factors that promote resistance to anti-angiogenic therapy in pediatric tumors.
Back to top
Jan Kitajewski, Ph.D. (Pathology & Cell Biology) - Signaling Pathways in Oncogenesis and Angiogenesis
The goal of the laboratory is to understand growth factor/receptor function in oncogenesis and tumor angiogenesis. The Wnt-1 growth factor was originally identified as a mammary oncoprotein in the mouse, and Wnt signaling components, most notably APC and beta-catenin, are involved in human colon, melanoma, and prostate cancers. The int-3 gene was also identified based on its oncogenic effects in the mouse mammary gland. This laboratory showed that the full-length gene encodes a cell surface receptor (Notch4) similar to the Notch/lin-12 proteins, and found that it can regulate the angiogenic process. Biochemical approaches and cellular systems are used to define the physiologic functions of the Wnt-1 and Notch4 proteins and the signaling pathways that carry out these functions.
Back to top
Anna Lasorella, M.D. (ICG) - Role of the N-Myc Oncoprotein in Neuroblastoma
Neuroblastoma is a very aggressive tumor of childhood marked by deregulation of the N-Myc oncoprotein due to gene amplification or increased gene expression. The aims of the laboratory are to define the mechanisms by which N-Myc is deregulated in neuroblastoma and to determine the contributions of N-Myc to neuroblastoma development. In the course of the work, the gene encoding helix-loop-helix protein Id2 was identified as a downstream transcriptional target of N-Myc and found to be essential for N-Myc-mediated cell transformation. Experiments are in progress to identify additional N-Myc target genes in neuroblastoma cells and characterize the N-Myc cellular complexes that promote neuroblastoma formation.
Back to top
Thomas Ludwig, Ph.D.(Pathology & Cell Biology) - Mouse Models of Hereditary Breast Cancer
Germline mutations of the BRCA1 and BRCA2 genes are implicated in hereditary breast and ovarian cancers. However, it remains unclear how loss of these genes confers susceptibility to tumorigenesis. The tumor suppressor gene p53 is mutated in a large number of BRCA-associated tumors, in accord with the hypothesis that inactivation of a cell cycle checkpoint is a necessary step and may precede BRCA loss during tumorigenesis. The focus of the laboratory is to study the biological function(s) of these proteins and their associated factors (including Bard1, Bach1, and CtIP) in vivo, using conditional mammary gland-specific mutagenesis in mice. These studies should 1) elucidate how functional inactivation of BRCA1/2 leads to breast and ovarian cancer, and 2) generate useful animal models of the human disease.
Back to top
Yinghui Mao, Ph.D. (Pathology & Cell Biology) - Chromosome Segregation and Aneuploidy
The goal of the laboratory is to take on the question of how faithful delivery of one copy of each chromosome is achieved as mammalian cells duplicate. Errors in this process cause abnormal chromosome numbers (aneuploidy) which are hallmarks of human tumor progression. We use in vitro Xenopus egg extracts that can reproduce most aspects of the cell cycle as well as mammalian cultured cells to identify the principle of chromosome segregation. The laboratory is studying the mechanisms of mitotic spindle formation, kinetochore microtubule attachment, and the mitotic checkpoint, a major cell cycle control mechanism that maintains genome intergrity.
Back to top
Rebecca Morris, Ph.D. (Dermatology) - Stem Cells and Skin Cancer
Dr. Morris’ interests and research focus on the epidermal and hair follicle stem cells of the skin and their role as target cells for carcinogens, ultraviolet light, and tumor promoters. One major effort in the lab is the identification and isolation of epidermal stem cells and target cells by means of a novel application of selection procedures. We have recently determined that living hair follicle stem cells can be selected by their expression of the blood stem/progenitor marker, CD34. CD34+ keratinocytes have stem cell characteristics of quiescence, high growth potential, and an ability to produce all the epithelial cell types in the skin. A second project is to determine the fate of hair follicle stem cells during the development of skin cancer. A third focus is to elucidate factors regulating the number of keratinocyte stem cells with an eye to identifying novel stem cell control genes. Our ability to identify and to isolate keratinocyte stem cells will enable us to determine how they behave in skin cancer, and to identify new genes that control epidermal growth, hair growth, and skin cancer development. Identification and isolation of the keratinocyte stem cells and their regulatory genes will also enhance efforts to design new treatments for skin cancer.
Back to top
David Owens, Ph.D. (Dermatology) - Stem Cells and Differentiated Cells in Epidermal Tumors
The laboratory is investigating the contributions of stem cells and differentiated cells to the development of epidermal cancer. In addition, the pathogenesis of these tumors is analyzed by 1) defining the influence of integrin receptors and TGF-beta on the epidermal tumor microenvironment and 2) comparing Ras signaling in subpopulations of epidermal basal cells with differing malignant potential.
Back to top
Ramon Parsons, M.D., Ph.D. (ICG) - Pathogenesis of Breast and Brain Cancer
The aim of the laboratory is to elucidate the molecular basis for human breast and brain cancers. The genetic lesions that lead a normal cell to develop into an advanced tumor are identified, and the genes targeted by lesions are analyzed to determine their normal function. In the course of this work a novel tumor suppressor gene, PTEN, was identified and shown to be mutated in breast, brain, prostate, and endometrial cancer. The present goals of the laboratory are to 1) study the normal functions of the PTEN gene, and 2) identify other tumor suppressor genes that are inactivated during breast and/or brain tumor development.
Back to top
Carol L. Prives, Ph.D. (Biological Sciences) - Function and Control of the p53 Tumor Suppressor
Mutation of the p53 gene is the most frequent lesion detected in cancer. The aim of the laboratory is to determine the function of p53 in normal cells and how mutations of p53 promote malignant transformation. The laboratory has shown that the p53 protein is a DNA-binding transcription factor that is activated in response to genotoxic stress by both covalent and non-covalent modifiers. Ongoing studies are exploring the signaling events by which genotoxic stress induces p53 activation, how p53 mediates its downstream functions of cell cycle arrest and apoptosis, and whether this information can be exploited to develop p53-based cancer therapeutics. In addition, the normal and malignant functions of the p53-related proteins, p63 and p73, are under investigation.
Back to top
Rodney J. Rothstein, Ph.D. (Genetics & Development) - Double-Strand DNA Break Repair and Genome Stability
DNA repair is an essential process for preserving genome integrity in all organisms. Not surprisingly, the cellular pathways that mediate DNA repair are highly conserved. The aim of the laboratory is to understand how double-strand DNA breaks (DSBs) are repaired by homologous recombination (HR) in yeast and how disruption of this process promotes oncogenesis in mammals. The laboratory has used yeast genetics to identify factors that mediate DSB repair and cellular methods to determine their spaciotemporal relationships during the DNA damage response. Since disruption of DSB repair is a common aspect of the genomic instability associated with cancer, the laboratory is also using mammalian systems to study the mammalian orthologs of these repair factors and evaluate their functional status in human tumors. This approach allows the power of yeast genetic screens to be exploited to understand the sources of genome instability in cancer.
Back to top
Regina P. Santella, Ph.D. (Environmental Health Sciences) - Gene-environment Interactions and Cancer Risk
The aim of this laboratory is to elucidate the role of environmental exposures and genetic susceptibility in the etiology of human cancers. This entails development of antibodies and immunologic methods for biological monitoring of human exposure to environmental and occupational carcinogens by measurement of their DNA and protein adducts. High-throughput genotyping for single nucleotide polymorphisms in DNA repair and carcinogen-metabolizing genes as well as DNA repair phenotyping methods are being used to understand susceptibility. The role of environmental agents in epigenetic alterations in methylation is also being investigated. These studies take advantage of biospecimens collected in a number of epidemiologic studies of breast, liver, lung and prostate cancer.
Back to top
Michael Shen, Ph.D. (Medicine) - Prostate Stem Cells and Cancer Stem Cells
The laboratory investigates the molecular mechanisms involved in prostate organogenesis and regeneration, as well as cancer initiation and progression. A primary focus of ongoing studies is the role of prostate epithelial stem cells and related progenitor cell types in these processes. Using targeted conditional and inducible mice to perform lineage-marking and cancer modeling, the laboratory has identified a novel epithelial progenitor cell population that can also serve as a cell type of origin for prostate cancer. Ongoing studies aim to identify key signaling pathways that regulate proliferation and differentiation of these progenitor cells, and to determine their relationship to putative cancer stem cells during carcinogenesis. Additional studies will examine the roles of analogous cell populations in the genesis of human prostate cancer, and will assess the abilities of potential therapeutics to target these progenitor cells.
Back to top
Saul Silverstein, Ph.D. (Microbiology) - Cell Transformation by Human Papillomaviruses
The ability of high-risk human papillomaviruses (HPV) to promote cervical carcinoma is dependent on expression of the viral E6 and E7 proteins. E6 expression promotes cell transformation in part by targeting p53 for ubiquitination and degradation. To elucidate additional mechanisms by which E6 contributes to carcinogenesis, the laboratory is examining other cellular pathways disrupted by E6 expression. Several unique host proteins that interact with the E6 protein from low and/or high risk HPVs have been identified and shown to be ubiquitinated in response to their interaction with E6 and the cellular E6AP ubiquitin ligase. The cellular pathways affected by ubiquitination of these proteins are under investigation to evaluate whether their disruption by E6 expression is a contributing factor in HPV-mediated carcinogenesis.
Back to top
Brent Stockwell, Ph.D. (Biological Sciences) - Diagramming the Signaling Networks of Cancer Cells
The aim of the laboratory is to diagram the interconnected signaling networks underlying cancer by using chemical and biological tools. The approach is to design high-throughput screens in mammalian cells that allow tens of thousands of small organic molecules and small interfering RNAs to be tested for their ability to affect cellular phenotypes associated with oncogenic signaling. These screens yield reagents that are used to identify specific proteins and genes that act as the critical regulators of tumor formation and progression. The molecular functions of these regulators are then studied using protein biochemistry, molecular cell biology, and chemical synthesis. Potential research projects include 1) creating and executing high-throughput screens related to oncogenic signaling to identify novel compounds of interest, 2) identifying the protein targets and signaling pathways affected by the compounds discovered in these screens, and 3) developing novel photoaffinity reagents, fluorescent sensors and chemical libraries.
Back to top
Gloria Su, Ph.D. (Pathology & Cell Biology) - Molecular Genetics of Pancreatic Tumors
The aim of this laboratory is to identify the molecular lesions responsible for pancreatic ductal adenocarcinoma and to develop faithful mouse models of the disease. Similar studies of head and neck squamous cell carcinoma (HNSCC) are also in progress. HNSCC and pancreatic ductal adenocarcinoma share defects in some common oncogenes and tumor-suppressor genes (e.g. p16 and p53), but each is characterized by unique tumor-associated mutations (e.g. cyclin D1 for HNSCC and K-Ras for pancreatic cancer). The laboratory uses genome scanning and candidate gene approaches to further define the molecular genetics of these tumor types. In addition, animal models of HNSCC and pancreatic ductal adenocarcinoma are being developed by generating mouse strains bearing targeted lesions in the implicated oncogenes and tumor suppressor genes.
Back to top
Lorraine Symington, Ph.D. (Microbiology) - DNA Recombination and Genomic Instability
Defects in double-strand DNA break (DSB) repair by homologous recombination contribute to genomic instability in many human tumors. The goal of the laboratory is to identify and characterize proteins that catalyze homologous recombination in eukaryotes. The yeast S. cerevisiae is used as a model system because it is readily manipulated genetically and biochemically, and shows a high frequency of mitotic and meiotic recombination. Moreover, since these processes are highly conserved, insights can be gained that are relevant to higher eukaryotes. For example, the laboratory has shown that MRE11, a key mediator of mitotic and meiotic recombination, is an endonuclease, but that its nuclease activity is required for meiotic, but not mitotic, recombination. This information is vital to understand the mammalian MRE11 complex, disruptions of which are responsible for two human cancer predisposition syndromes (AT-like disease and Nijmegen breakage syndrome).
Back to top
Benjamin Tycko, M.D., Ph.D. (ICG) - Genetic and Epigenetic Defects of Wilms Tumors
The aim of the laboratory is to identify genetic lesions responsible for Wilms tumor and determine how defects of genetic imprinting influence promote Wilms’ tumor and other embryonal tumors. Fetal and placental growth is controlled by a cluster of imprinted genes on chromosome 11p15 (the IGF2/H19 locus). Significantly, most Wilms tumors show either loss of heterozygosity for 11p15 alleles or loss of imprinting at the IGF2/H19 locus. The laboratory is investigating the characteristic epigenetic abnormalities of Wilms tumors caused by increased methylation of the H19 gene, including loss of H19 expression and biallelic expression of the oppositely imprinted IGF2 gene. In addition, gene expression profiles are being used to discern distinct classes of Wilms’ tumor and to define the molecular lesions that distinguish these tumor subtypes.
Back to top
Timothy Wang, M.D. (Medicine) - The Pathogeneis of Gastrointestinal Cancers
The aim of the laboratory is to understand the role of inflammation and growth factors in the development of gastrointestinal cancers, with particular emphasis on Helicobacter-mediated gastric cancer. Five major projects relevant to gastrointestinal cancers are currently under investigation: 1) Helicobacter pylori and gastric cancer, 2) function and regulation of trefoil factor-2, 3) regulation of histidine decarboxylase and histamine in the stomach, 4) the role of gastrin in colorectal cancer, and 5) the origin of cancer stem cells.
Back to top
Debra J. Wolgemuth, Ph.D. (Genetics & Development) - Cyclin A1 and Acute Myeloid Leukemia
The laboratory identified a novel mammalian A-type cyclin, cyclin A1, and showed 1) that it is expressed primarily if not exclusively in the testis of mice and humans and 2) that targeted mutagenesis of the cyclin A1 gene results in viable progeny with male sterility. Interestingly, cyclin A1 is highly expressed in human leukemic cells from patients with acute myeloid leukemia (AML). Moreover, transgenic mice in which cyclin A1 overexpression was targeted to myeloid precursor cells displayed abnormal myelopoiesis and developed AML. The laboratory is now exploring whether cyclin A1 overexpression is a causative factor in AML and whether pharmacological inhibition of cyclin A1/Cdk has therapeutic value for treatment of human AML.
Back to top
Darrell Yamashiro, M.D., Ph.D. (Pathology & Cell Biology) - Anti-angiogenic Therapy for Pediatric Tumors
The Pediatric Tumor Biology Laboratory, co-directed by Drs. Yamashiro and Kandel, focuses on the role of angiogenesis in promoting the growth and metastasis of pediatric solid tumors. To test the effect of blocking angiogenesis in pediatric tumors, xenograft models of neuroblastoma, Wilm’s tumor, hepatoblastoma, and rhabdoid tumor of the kidney were developed. With these systems, the laboratory has shown that blocking vascular endothelial growth factor (VEGF) markedly suppresses the growth of microscopic tumors by inhibiting angiogenesis. The xenograph models are now being used to determine the mechanisms by which anti-angiogenic agents suppress tumor growth, and to identify factors that promote resistance to anti-angiogenic therapy in the different pediatric tumors.