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Section Faculty Mentors and Their Research Interests
Eric C. Beyer, PhD, MD
Professor of Pediatrics, Cell Physiology, Cancer Biology, and Molecular Medicine
Director, Pediatric Hematology/Oncology Fellowship Program
Chairman, Committee on Cell Physiology
Cellular biology and physiology of intercellular communication mediated by gap junction channels; arrhythmias; cataracts; tumor cell apoptosis.
ecbeyer@uchicago.edu
»Research details
Rena Conti, PhD
Instructor in Pediatrics
Health economics: studies of the value of new medical technology for individuals and society and the organization and financing of medical care for vulnerable populations, including children and the mentally ill.
rconti@peds.bsd.uchicago.edu
Susan L. Cohn, MD
Professor of Pediatrics and Cancer Biology
Director of Clinical Research, Section of Pediatric Hematology/Oncology
Institutional Principal Investigator, Children’s Oncology Group
Clinical trials for patients with neuroblastoma; laboratory investigation of neuroblastoma biology: tumor stroma/SPARC; epigenomics
scohn@peds.bsd.uchicago.edu
»Research details
John M. Cunningham, MD
Professor of Pediatrics and Developmental Biology
Chief, Section of Pediatric Hematology/Oncology
Clinical trials in hematopoietic stem cell transplantation and for treatment of genetic diseases; laboratory investigations of the biology and therapy of hemoglobinopathies; transcriptional mechanisms during vertebrate development
jcunning@peds.bsd.uchicago.edu
Christine Hartford, MD
Assistant Professor of Pediatrics and Clinical Pharmacology
Phase I trials of new agents in pediatric patients with malignancies; adolescent and young adult oncology; clinical pharmacology and pharmacogenomics of anticancer agents
chartford@peds.bsd.uchicago.edu
Tara Henderson, MD, MPH
Assistant Professor of Pediatrics
Director, Childhood Cancer Survivors Center
Clinical care and surveillance of childhood cancer survivors; investigations of the development of second malignancies
thenderson@uchicago.edu
»Research details
Eneida Mendonça, MD PhD
Associate Professor of Pediatrics and in the Computational Institute
Biomedical informatics: translation of scientific evidence into clinical practice; use of computational methods and informatics techniques to analyze large biomedical data sources.
emendonc@peds.bsd.uchicago.edu
James Nachman, MD
Professor of Pediatrics
Clinical trials of treatments for pediatric leukemia, Hodgkin lymphoma, osteogenic sarcoma
jnachman@peds.bsd.uchicago.edu
Kenan Onel, MD, PhD
Assistant Professor of Pediatrics and Cancer Biology
Director, Pediatric Familial Cancer Clinic
Genetics of cancer susceptibility: identification of the genetic determinants of apoptosis and the p53 network of apoptosis; biomarkers and therapeutic targets in pediatric leukemia; genomic susceptibility loci in secondary leukemia
konel@peds.bsd.uchicago.edu
»Research details
Charles Rubin, MD
Associate Professor of Pediatrics
Brain tumors; clinical trials of treatment for childhood cancers.
crubin@peds.bsd.uchicago.edu
Ruth Rudinsky, MD
Clinical Associate in Pediatrics
Outpatient care for children with cancer and blood disorders.
rrudinsk@peds.bsd.uchicago.edu
Stephen X. Skapek, MD
Associate Professor of Pediatrics and Cancer Biology
Director of Oncology
Clinical trials for children with rhabdomyosarcoma and other soft tissue sarcomas; laboratory investigation of rhabdomyosarcoma cell cycle regulation; ARF tumor suppressor gene and blood vessel growth
sskapek@peds.bsd.uchicago.edu
Uma Subramanian Srinivasan, MD
Assistant Professor of Pediatrics
Director, Pediatric Sickle Cell Program
Clinical care for patients with all types of blood disorders, especially sickle cell anemia.
usrin@peds.bsd.uchicago.edu
Samuel L. Volchenboum, MS, MD, PhD
Instructor in Pediatrics and the Computational Institute
Informatics; proteomics; neuroblastoma
svolchen@peds.bsd.uchicago.edu
Faculty Research Details
Eric C. Beyer, PhD, MD
Professor of Pediatrics, Cell Physiology, Cancer Biology, and Molecular Medicine
Director, Pediatric Hematology/Oncology Fellowship Program
Chairman, Committee on Cell Physiology
My laboratory is investigating the process of intercellular communication; our specific goal is a molecular understanding of the structure and function of gap junctions. Gap junctions are the specialized plasma membrane structures that contain low resistance channels linking adjacent cells. In excitable tissues, they permit electrical coupling; in non-excitable tissues, they permit passage of small molecules involved in metabolic support, growth control, and embryogenesis. They may also facilitate drug metabolite delivery between cells. Gap junctions are encoded by a family of subunit proteins called connexins which are related in their transmembrane and extracellular regions, but which have unique cytoplasmic domains. Connexin-specific sequences confer different physiologic channel properties or regulation. Mutations of connexins have been associated with a number of diseases including non-syndromic deafness, Charcot-Marie-Tooth disease (neuropathy), cataracts, oculodentodigital dysplasia, and skin diseases.
In vitro expression studies and transgenic mouse studies are being used to examine the consequences of disease-associated connexin mutations.
The transfection of communication-deficient cells with connexin sequences (or expression of in vitro transcribed connexins in Xenopus oocytes) has demonstrated connexin-specific channel properties, permeabilities, and regulation. Site-directed mutagenesis is being used to identify sites within the connexins important in determining gating and permeability properties. We are also studying the sequences involved in oligomerization and cellular trafficking.
We are using adenoviruses to express connexins in endothelial cells and other mature cell types to examine the roles of intercellular communication in these cells. We are using in situ hybridization to study the roles of connexins in embryonic development. We are examining the role of connexins and intercellular communication in cell viability and apoptosis.
Susan L. Cohn, MD
Professor of Pediatrics and Cancer Biology
Director of Clinical Research, Section of Pediatric Hematology/Oncology
Institutional Principal Investigator, Children’s Oncology Group
Dr. Cohn’s research interests are focused on understanding the biology of neuroblastoma, a clinically heterogeneous childhood cancer, and identifying new potential therapeutic targets. One research project ongoing in Dr. Cohn’s laboratory involves the analysis of angiogenesis in neuroblastoma. Dr. Cohn’s laboratory was the first to report the correlations between high vascular density in neuroblastoma tumors and advanced stage disease, unfavorable histology, MYCN amplification, and poor outcome. These studies also demonstrated that the vascularity of stroma-rich tumors is low. More recent studies have demonstrated structural abnormalities including vascular endothelial cell proliferation (VEP) in neuroblastoma tumors that are clinically aggressive. Interestingly, VEP was not detected in Schwannian stroma-rich tumors, further suggesting that angiogenesis is regulated differently in Schwannian stroma-rich versus stroma-poor NB tumors. Dr. Cohn’s lab has determined that Schwann cells, derived from stroma-rich neuroblastoma tumors, produce a number of angiogenic inhibitors including Secreted Protein Acidic and Rich in Cysteine (SPARC). Preclinical studies have shown that SPARC is capable of inhibiting angiogenesis and neuroblastoma growth, and potent anti-angiogenic activity is also seen with a peptide that was designed to correspond to the epidermal growth factor-like module of the follistatin domain of SPARC. The Cohn lab has also shown that treatment with a number of anti-angiogenic agents are capable of “normalizing” the architecture and function of neuroblastoma blood vessels, suggesting that this treatment strategy may also allow for more efficient cytotoxic drug delivery.
In addition to angiogenesis, interactions between malignant cells and other tissues in the tumor stroma also influence tumor growth. The normal host microenvironment is non-permissive for neoplastic progression, whereas tumor-reactive stroma, characterized by the presence of activated fibroblasts, promotes neoplastic growth and metastasis. The Cohn lab has recently shown that SPARC prevents fibroblast activation, suggesting that in addition to blocking angiogenesis, SPARC may inhibit tumor growth by promoting the assembly of stroma that is non-permissive for tumor progression. Studies elucidating the mechanisms by which SPARC modifies the tumor stroma leading to a non-permissive microenvironment for tumor growth are ongoing.
Epigenomics is a second area of research emphasis in the Cohn lab. The methylation status of genes that are frequently epigenetically inactivated in adult cancers have been evaluated in neuroblastoma cell lines and primary tumors. The tumor suppressor gene RASSF1A is epigenetically inactivated in a subset of neuroblastoma tumors and cells lines. RASSF1A methylation is significantly associated with poor survival, suggesting that abnormal silencing of this gene may play a role in neuroblastoma pathogenesis. Additional studies on primary neuroblastoma tumors have shown that methylation of CASP8, DCR2 and Hin-1 are also associated with high-risk disease and poor outcome. Studies analyzing the prognostic and functional significance of epigenetically silenced genes in neuroblastoma are ongoing.
Tara Henderson, MD
Assistant Professor of Pediatrics
Director, Childhood Cancer Survivors Center
Treatment of childhood malignancies has become increasingly successful with a current overall cure rate approaching 80%. With cure, come the long-term toxic late effects of chemotherapy and radiation during critical periods of development, including second cancers and damage to vital organ systems. My clinical and research area of focus is in survivors of pediatric cancer. My primary focus has been in the development of and screening for second cancers following childhood cancer.
Project 1:
Second Sarcomas following Childhood Cancer
Childhood cancer survivors are at increased risk of development of secondary neoplasms, and exposure to radiotherapy is a known risk factor. The true incidence of secondary sarcomas, as well as other risk factors for their development, has not been well-described. With this in mind, I developed and implemented two studies investigating second sarcomas in the Childhood Cancer Survivor Study (CCSS). The CCSS, an NIH funded resource, is the largest, most comprehensive cohort study of childhood cancer survivors to date, and allows correlation of primary treatment data with current demographic and health information in over 14,000 survivors of childhood cancer.
My first study is a cohort study examining 108 bone and soft-tissue sarcomas in 104 CCSS participants which is the largest series of second sarcomas ever assembled in the literature. I orally presented my preliminary findings at the American Society of Clinical Oncology last spring and won a merit award for my work. In my position at the University of Chicago, I completed the data analysis and now have prepared the manuscript of the study.
I have also developed a case-control study in the CCSS examining the radiation-dose effect in the development of this series of sarcomas. Together with the radiation oncology research team at MD Anderson Cancer Center lead by Marilyn Stovall, PhD, I have completed reviewing the 108 sarcomas described above such that they have been diagrammed for dosimetry analysis. The CCSS has reported over 20 new sarcomas since my initial analysis and I am currently reviewing these second cancers to be included in this analysis. We expect the dosimetry studies to be completed by early autumn 2006 and the final statistical analysis and manuscript preparation to occur shortly thereafter.
Project 2:
Breast Cancer and Breast Cancer Screening Following Radiation to the Chest for a Pediatric Malignancy
In brief, women who received chest irradiation for a pediatric cancer develop breast cancer at younger ages, with rates equaling BRCA I/II mutation carriers. By consensus, mammography is the recommended screening modality beginning at age 25 years. Small series have been reported as detecting breast cancer in this population with mammography. However, the current rates of screening in women <40 years (the age at which screening is recommended in the general population) are largely unknown. Further, some studies in survivors at risk indicate they are unaware of their high risk of breast cancer. We are interested in understanding the practice and effectiveness of current screening practices for breast cancer in women with a history of chest radiation for pediatric cancer, with the ultimate goal of amending current screening guidelines, and developing a three-arm intervention trial educating breast cancer survivors regarding risk and appropriate screening.
Currently, under the auspices of the COG (244-institution clinical trials consortium) Late Effects Cancer Screening Working Group, Dr. Kevin Oeffinger and I conducted a systematic review of the literature to answer three questions: (1) What is the risk of breast cancer in women who have been treated with chest radiation for a pediatric cancer; (2) What are the outcomes of breast cancer in women in this population; (3) Does breast cancer screening change outcomes? The data is currently being compiled and the manuscript drafted.
Through the CCSS, Dr. Kevin Oeffinger is leading a research team of which I am a co-investigator, to assess the mammogram screening practices, health beliefs, and barriers and facilitators to screening mammography in 700 women, age 25-49, who were treated with chest radiation for a pediatric cancer and two standard risk comparison groups.
Further, I have developed a concept proposal for a retrospective descriptive study the methods of detection of the 127 women who developed breast cancer in the cohort following chest radiation for a pediatric cancer (the largest series of such women worldwide).
I am also working with Dr. Funmi Olopade’s cancer risk clinic at the University of Chicago to follow our female survivors who received radiation therapy. Currently, through this clinic, there is an open study examining the sensitivity and specificity of MRI versus mammogram in women identified at high risk for breast cancer. We have amended the study to include women who received irradiation to the chest prior to age 30.
Project 3:
Intermediate Hodgkin’s Disease Therapy to Minimize Late Effects
Recently, I have been asked to Chair the new Children’s Oncology Group study for intermediate risk Hodgkin’s disease. Currently Hodgkin’s disease carries cure rates approaching 90%. With cure, have come late effects including high rates of early breast cancer and early cardiac disease, most often associated with radiation therapy. We are currently designing the COG protocol to determine early response to chemotherapy using PET imaging, with the ultimate aim of preventing the need for radiotherapy in this cohort of young patients.
Kenan Onel, MD, PhD
Assistant Professor of Pediatrics and Cancer Biology
Director, Pediatric Familial Cancer Clinic
The goal of Dr. Onel’s research is to understand the genetic basis of cancer susceptibility with the ultimate objective of developing individualized cancer prevention strategies and targeted therapies.
Cancer results from a mutation or a series of mutations that cause a cell to escape from normal regulatory controls. Cellular stresses such as DNA damage vastly increase the rate of mutation, and therefore, the likelihood of malignant transformation. Apoptosis, or programmed cell death, is the primary cellular mechanism to counter the cancer-causing potential of these stresses. In light of the critical role played by apoptosis in the prevention of the cellular transition from normal to cancer, Dr. Onel’s studies have focused on pathways of apoptosis.
The major projects underway in his laboratory are:
- The identification of the genetic determinants of apoptosis
- The identification of the p53 network of apoptosis
- The identification of novel biomarkers and therapeutic targets in pediatric leukemia
- The role of candidate apoptosis-related genes and SNPs in cancer and autoimmune disease
