Oncology; Cell Cycle; Cell growth, differentiation and development; Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Signal Transduction; Transcription and Translation
Protein phosphorylation is an essential mechanism by which intercellular signals regulate specific intracellular events. Protein kinases, the enzymes catalyzing protein phosphorylation reactions, represent a major superfamily of genes, collectively representing 2% of the protein coding potential of the human genome. Current projects in Dr. Edelman‘s lab are devoted to the role of protein kinases in neuronal development and in specific types of cancer. These projects utilize a wide range of techniques and involve, in the case of the latter focus, a collaboration with investigators at Roswell Park Cancer Institute to develop a protein kinase-targeted therapy for prostate cancer.
Research and Professional Goals: 1. Clilnical research program: Our work at Roswell Park Cancer Institute focuses on translational research in breast cancer diagnosis and treatment, including collaborations with other clinicians and scientists in biological markers of cancer and cancer progression. 2. Health Services Research: Using a variety of data sources, we are working on methods to define and improve the quality of cancer care. The models used for this work include administrative claims data from regional payers, and multi institutional databases through national consortiums. 3. Clinical activities: We maintain a high volume, multidisciplinary program in breast cancer diagnosis and treatment at Roswell Park Cancer Institute. Teaching, clinical trials and translational research are integrated into this program at all levels.
Ear, Nose, Throat (Otolaryngology); Oncology; Plastic Surgery for Head (Ear, Nose,Throat); Cell growth, differentiation and development
Wesley L. Hicks Jr., M.D., is chair of the Head and Neck/Plastic & Reconstructive Surgery Program at Roswell Park Cancer Institute in Buffalo, NY. Dr. Hicks is Board Certified by the National Board of Medical Examiners and the American Board of Otolaryngology. He is also a tenured Professor of Otolaryngology/Head and Neck Surgery and Professor of Neurosurgery and Bioengineering at the University at Buffalo School of Medicine and Biomedical Sciences. His research interests focus on tissue engineering, wound healing and mechanisms involved in wound repair. His laboratory is studying novel work in bioengineered devices for enhanced wound repair, as well as cellular microenvironment effecting tissue remodeling and repair. Dr. Hicks was recently named one of the nation’s Top Cancer Doctors by Newsweek magazine and is a recipient of the American Academy of Otolaryngology’s Head and Neck Surgery Honor Award. He was also selected as one of the top 100 physicians in the nation by Black Enterprise magazine. He earned his dental degree at Meharry Medical College and his medical degree at the University at Buffalo School of Medicine and Biomedical Sciences. He completed his residency in Otolaryngology, Head & Neck Surgery at the Manhattan Eye, Ear and Throat Hospital, New York Hospital — Cornell Medical Center, Memorial Sloan-Kettering Cancer Center, New York, NY, and his Fellowship in Head & Neck Surgery at Stanford University Medical Center, Palo Alto, CA. Dr. Hicks is a member of a number of professional organizations, including the National Medical Association, the Triologic Society, the American Medical Association, the American Academy of Otolaryngology/Head & Neck Surgery, the American College of Surgeons, the American Head & Neck Society, and the Society of Black Academic Surgeons. He was a Senior Examiner for the American Board of Otolaryngology. His community affiliations include board memberships on the Board of Directors of HealthNow Inc./BlueCross BlueShield of New York State, the Urban League, the advisory board of First Niagara Bank and WBFO — the National Public Radio (NPR) affiliate. He also is a Commissioner of the Niagara Frontier Transportation Authority. Dr. Hicks has authored or co-authored more than 200 journal publications, book chapters and abstracts, and has been issued a number of patents related to his interest in tissue engineering and wound healing.
My current research interests and expertise are in the following areas: limb salvage for sarcomas and other tumors; node dissections in malignant melanoma; regional chemotherapy; debulking of disseminated abdominal tumors; intraperitoneal chemotherapy; intraoperative radiation; resection of difficult or unresectable tumors. 1)resection of difficult "unresectable" tumors which can be rendered resectable through special surgical techniques; e.g. retroperitoneal sarcoma limb preserving surgery and resection of extremity sarcomas. 20 surgical treatment of malignant melanoma, stages I-IV. Other research interestes: 1) Tumor Immunology; 2) Regional chemotherapy; 3) The development of a predictable, reliable chemosensityiveity assay in vitro.
Infectious Diseases; Oncology
I care for hospitalized patients and outpatients at Roswell Park Cancer Institute (RPCI), where I am head of Infectious Diseases. My area of clinical expertise relates to infections in patients with cancer and stem cell transplant recipients, and I have served on several national panels that establish guidelines for preventing, diagnosing, and managing infections in these patients. I also have a specific interest in patients with primary phagocytic disorders (e.g., chronic granulomatous disease). RPCI is the site of my clinical teaching. I also teach medical students in lecture settings and in small group sessions in their first and second years, including courses in lung pathophysiology and microbiology-immunology. We intermittently have students in our lab and participate in a grant designed to encourage medical students to become physician-scientists. I mentor residents in their clinical training and in research. I also teach fellows in all aspects of their training and mentor those who perform their research projects in my lab. I have an active, nationally funded translational research program. The major focus of our lab is studying NADPH oxidase as a critical regulator of inflammation and host defense. NADPH oxidase is an emergency host defense pathway that is rapidly activated in response to certain microbial products, and converts molecular oxygen to superoxide anion and downstream reactive oxidant intermediates (ROIs). Chronic granulomatous disease is an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal infections (e.g., invasive aspergillosis) and by excessive inflammation. In addition to its critical host defense role, our lab, in collaboration with colleagues, found that NADPH oxidase also functions to restrain inflammation by modulating redox-sensitive innate immune pathways. NADPH oxidase also affects T-cell responses, including the balance between Tn17 and regulatory T-cells. We have an NIH grant to further elucidate mechanisms by which NADPH oxidase regulates inflammation. We believe that our work has broad relevance to human diseases associated with inflammation, such as inflammation-induced injury and tumor immunology. Indeed, several of the pathways that NADPH oxidase regulates are important in tumorigenesis and the tumor microenvironment (e.g., NF-kB, Nrf2, IL-17, Tregs), and are potential therapeutic targets. In collaboration with colleagues, we are examining how NADPH oxidase influences tumor immunity.
Allergy and Immunology; Oncology
-Studies in this laboratory have established that trophoblast cells have developed two novel mechanisms of silencing MHC class II genes: an upstream negative-regulatory element controlled by two trophoblast specific DNA binding proteins, and repression of transcription of the class II transactivator (CIITA). Recently, some human tumor cells have been shown to have a trophoblast phenotype, in that CIITA and class II are not inducible with g-IFN or other cytokines. In collaboration with A. Latif Kazim and Carleton Stewart, RPCI, we have shown that tumor cell lines that are not responsive to g-IFN despite an intact g-IFN receptor and Jak-Stat signaling pathway, can be induced to express mRNA and cell surface class II with agents that acetylate histones and remodel chromatin structure. Unexpectedly, we found that class II induction by inhibitors of histone deacetylase occurred in the apparent absence of transcription of CIITA. Recent studies with mutant cell lines defective in established class II regulatory genes suggest the existence of a pathway independent of CIITA, the presumed master regulator of MHC class II. During these experiments, we also showed that the expression of two other molecules of immunological importance MHC class I and CD40 also were activated by histone deace-tylase inhibitors. Dr. William Magner has joined my laboratory recently and, together with Dr. Elizabeth Repasky, we extended these studies to different mouse tumor cell lines, and demonstrated by flow analysis the induction of MHC class I and II genes as well as the costimulator molecule CD40. We are exploring the spectrum of antigens expressed on tumor cells treated with histone deacetylase inhibitors including TGF-b receptors and tumor associated antigens. We are determining whether treated tumor cells administered in vivo show enhanced immunity and decreased tumorigenicity to subsequent challenge with wild type cells. In this regard, as first shown by Ostrand-Rosenberg, et al., mouse sarcoma I cells, when transfected with MHC class II, produce solid and long-lasting immunity to inoculation with wild type cells. Thus, these findings have significance in tumor escape mechanisms and the development of vaccines. We have explored the possibility that repressors of CIITA transcription exist in trophoblast and tumor cells, thus inhibiting class II expression and its induction by g-IFN. TGF-b1 and IL-10 are produced by all of the tumor cell lines we examined that were deficient in class II expression. Since these cytokines repress class II transcription by inhibiting CIITA transcription, the possibility of autocrine inhibition is suggested. The mechanisms of TGF-b repression may involve recruitment of deacetylase enzymes to the class II promoter site by CREB-CBP-CIITA complexes. This possibility will be explored using chromatin immunoprecipitation techniques. Studies have been initiated on the role of transcriptional cofactors with histone acetyltransferase activity, as well as the role of ATP-dependent multiprotein chromatin remodeling complexes in regulating MHC gene expression. Our work also has demonstrated that TGF-b can bind to receptors on dendritic cells and inhibit antigen presentation. Moreover, serum TGF-b1 levels are elevated in AIDS and DC cells derived from the blood of HIV patients who have high levels of cell surface TGF-b1. Treatment with anti-TGF-b, or anti-type III TGF-b receptor antibodies, or the addition of GM-CSF reverses the defect in antigen presentation in AIDS-PBL in vitro. Prelimin-ary clinical studies in patients with advanced AIDS, in collaboration with the Department of Medicine, have shown that GM-CSF reverses the antigen presentation defect and significantly raises CD4 cell numbers in many, but not all, AIDS patients. To test the hypothesis frequently quoted in the literature that aberrant expression of class II antigens on fetal trophoblast cells is responsible for most spontaneous abortions, transgenic animals are being prepared that will express class II on placental trophoblast cells at a specific time during gestation. We have cloned 300 bp of the proximal promoter of a trophoblast specific gene, 4311, and placed this in an expression plasmid upstream of the full-length CIITA gene. This construct was shown to be active when transfected into freshly isolated mouse spongiotrophoblast cells. Thus, mice bearing this transgene should begin to transcribe CIITA at day 6 of gestation when the 4311 gene is first expressed. If the hypothesis is correct, then MHC class II should be expressed by day 7-8, and abortion would occur. A dominant negative of CIITA has been produced by deletion of part of the activation domain of CIITA, and this could potentially be expressed in trophoblast cells of strains with high abortion rates. If as postulated by others, fetal loss in these abortogenic strains is due to aberrant expression of CIITA and subsequently class II, the dominant negative should inhibit abortions in these mice.