HEMATOLOGY/ONCOLOGY RESEARCH
Research Activities in the Hematology and Oncology Division |
The faculty in the hematology and oncology division has several research themes which include stem cell biology & therapeutics, apoptosis & autophagia, angiogenesis & vascular medicine, colon cancer genetics, therapeutic signaling targets in thoracic oncology, research on energetics and cancer, aging cancer research development program, and developmental therapeutics & investigator initiated clinical trials research
The Division of Hematology/Oncology has an exceptionally strong basic, translational, and clinical research programs and funding to division members of over eighteen million (18) dollars of annual direct support. This level of funding consists of individual NIH grants, programmatic grants for the Case Comprehensive Cancer Center (NCI), Center for Stem Cell and Regenerative Medicine (Ohio 3rd Frontier), National Center for Regenerative Medicine (NIH/HRSA), Developmental Therapeutics (U01), Programs in Aging Cancer Research (NCI), Research on Energetics (NCI), a Howard Hughes Institute Award to Dr. Sandy Markowitz, and Pharmaceutical sponsored research that is coordinated through the Ireland Cancer Center.
The research programs of the Division are aligned such that it provides for a critical mass of investigators for collaborative research efforts and opportunities for further growth development and recruitment.
Stem Cell Biology and Therapeutics
Drs. Gerson, Lazarus, Laughlin, Liu, Bunting, Qu,
These investigators study hematopoietic stem cells (HSC), umbilical cord blood stem cells (UCB), and mesenchymal stem cells (MSC). Dr. Gerson, former division chief and present cancer center director, studies drug selection, stem cell gene transfer and its impact on engraftment in vivo in both animal and human systems. Dr. Gerson also discovered that a mutant form of the DNA repair gene, MGMT would confer resistance to chemotherapy to HSC’s. Gene transduction followed by stem cell transplantation increases engraftment into marrow and more recently in the lung following drug selection in vivo in mice. Dr Gerson’s investigator-initiated research includes showing declining DNA repair in aging hematopoietic stem cells and gene transfer into hematopoietic progenitors. He and Dr. Liu also are investigating modulation of base excision repair in tumor drug resistance and have a research plan for Tracon - methoxymine combined with gemcitabine, 5FU or Alimta.
Drs. Lazarus, and Gerson have studied MSC cell therapy. Dr. Lazarus has evaluated the impact of MSC’s on reducing the incidence of graft vs. host disease (GVHD) in patients undergoing allogeneic transplantation in malignancy. Dr. Lazarus also heads the Stem Cell Transplant Program and is a member of a twelve-center consortium for stem cell transplant clinical trials across the nation. This activity is an important national collaboration program that encourages large studies to ask important questions in the field of stem cell transplantation.
Dr. Bunting evaluates/STAT signaling in hematopoietic stem cells using animal models and has documented the remarkable impact of loss of STAT 5 signaling on hematopoiesis. Current work is evaluating the role of STAT5 in non-myeloablative conditioning, structure-function relationships of STAT5 in hematopoiesis, and the role of STAT5 in leukemic cell survival. Further investigations examine the role of TIMPS in hematopoietic stem cell biology.
Dr. Qu is examining how mutations in SHP-2 influence the development of juvenile leukemia and how SHP-2 inhibitors may be potential therapeutic agents for JMML and Noonan Syndrome. He is also developing novel small molecule inhibitors to SHP-2.
Dr. Laughlin studies the immunologic reactions of UCB and has found reduced expression of NFAT, a key immune signaling regulator. Her laboratory has interest in lymphocyte biology as it pertains to GVHD and is investigating cord blood stem cell transplantation to support underserved populations.
Apoptosis & Autophgia
(Drs. Distelhorst, Matsuyama)
Dr. Distelhorst investigates the fundamental mechanisms through which glucocorticosteroid hormones induce apoptosis and autophagy in lymhoma cells. Through gene expression analysis his laboratory has discovered many of the genes involved in mediating these processes. An additional area of research is into the function of the anti-apoptotic protein Bcl-2, which his laboratory discovered interacts with the inositol 1,4,5-trisphosphate receptor and regulates intracellular calcium signals.
Dr. Matsuyama studies the apoptotic process and has identified a number of intermediate signaling molecules that interact with bax, bcl2, and bad all-important molecules that migrate towards the mitochondria during the early phases of apoptosis and apoptotic blockade. He has developed a small peptidomimetic that blocks the function of that and alters apoptotic signaling.
Angiogenesis and Vascular Medicine
Drs. McCrae, Nieman, Schmaier
Dr. McCrae basic research program explores several areas of vascular biology, with a general focus on biology of the endothelial cells. One program focuses on the mechanisms by which the cleaved form of high molecular weight kininogen (HKa) functions as an endogenous regulator of angiogenesis. These studies investigate the nature of the interactions between HKa and proliferating endothelial cells in an attempt to define the pathways by which HKa induces endothelial cell apoptosis. The laboratory has developed a kininogen-deficient mice in which angiogenesis and tumor growth are enhanced; the mechanisms by which this occurs is under active investigation. A second project involves characterization of the interactions of anti-β2GPI antibodies with endothelial cells. These antibodies are the primary type of antiphospholipid antibody that causes thrombosis in patients with the antiphospholipid syndrome (APS). The laboratory has demonstrated that these antibodies cause endothelial cell activation through cross linking of β2GPI bound to endothelial cell annexin A2. This pathway appears to involve activation of TLR4/NF-κB signaling pathways. In addition, clinical studies are focused on defining the role of circulating cellular microparticles (platelet, endothelial cell, monocyte) as markers of vascular damage or activation in APS, cancer and recurrent fetal loss.
Dr. McCrae also leads a clinical research program in hematology, the core of which is a multicenter NHLBI program in transfusion medicine and hemostasis. Several clinical research protocols in involving heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura, and other disorders are currently in progress. Separately, Dr. McCrae directs several pharmaceutical-based studies involving new thrombopoetin analogues, new agents for the treatment of hemophilia, as well as other approaches to the care of patients with hematologic disease.
Dr. Schmaier, current division chief, investigates the regulation of bradykinin delivery on endothelium and its influence on vascular biology in relation to thrombosis, hypertension, and angiogenesis. Presently studies are characterizing several mouse models that influence thrombosis risk without affecting hemostasis. Dr. Schmaier has recognized novel interactions between the plasma kallikrein/kinin and renin angiotensin systems on how they influence thrombosis risk. In particular, he is characterizing mechanisms by which the bradykinin B2 receptor knockout mice are protected from arterial thrombosis. Further, his laboratory is examining the prothrombotic and hypertensive phenotype of the prolylcarboxypeptidase murine hypomorphs. His laboratory has developed a novel direct thrombin inhibitor and thrombin receptors activation antagonists called “Thrombostatins” derived from the angiotensin converting enzyme breakdown product of bradykinin. The current lead compound is orally available and can prevent thrombosis and cancer growth in vivo. Last, Dr. Schmaier’s laboratory is examing the mechanism of outside-in signaling in the plasma kallikrein/kinin system on endothelium and how stimulation of the urokinase plasminogen activator receptor results in cell growth, proliferation, and angiogenesis in vitro and in animal models.
Dr. Nieman investigates the structure and function of protease activated receptors 1 and 4 and their physical and functional interrelationships.
Colon Cancer Genetics
Markowitz MD, Sanford
Dr. Markowitz,a Howard Hughes Investigator, leads a multidisciplinary team of investigators in comprehensive studies of colon cancer etiology prevention and treatment. His laboratory has played a key role in discovering the role of the TGF-beta pathway as a tumor suppressor of gastrointestinal cancers and a target of inactivating mutations in human cancers. He has also discovered the role of the 15-PGDH gene as a tumor suppressor in multiple cancers and as an effector of the TGF-beta pathway. His laboratory additionally has made important contributions to the discovery of novel targets of aberrant methylation in cancer, to the discovery of new genetic loci linked to familial risk of colon cancer, and to the investigation of the genetics of metastasis of colon cancer. Most recently the Markowitz laboratory has discovered a novel molecular diagnostic for early detection of colon cancer, through detection of aberrantly methylated DNA in patient feces. This test is currently being introduced nationally for use in the clinic.
Therapeutic Signaling Targets in Thoracic Oncology
Drs. Dowlati, Halmos, Ma
Dr. Dowlati, the leader of the thoracic oncology group, studies the EGFR pathway and inhibitors and Erb B2. He has a discovered that over expression of Erb B2 and STAT 3 is important in the maintenance of lung cancer cells and inhibiting both signal pathways is important in blocking cell growth and proliferation. He has further defined that the majority of lung cancers over express both signaling molecules and has found that using inhibitors of both molecules provide much greater synergistic cytotoxicity than either molecule alone. Dr. Dowlati also is an active translational investigator being the PI on a number of investigator-initiated Phase I studies and several Phase II and III grants:
Dr. Halmos also investigates the role of the EGFR/ErbB2 pathway in thoracic oncology. In addition to studies on it role in non-small cell lung cancer, he has been examining the identification of genetic abnormalities of the EGFR/ErbB2 pathway in Barrett’s esophagus and esophageal adenocarcinoma. Further he has been studying the development of stem cell model systems of lung cancer and tobacco-damaged epithelium.
Dr. Patrick Ma studies the role of c-MET in small cell lung cancer. He is actively involved in the developing a high-throughput cell-based MET inhibitor development for individualized lung cancer therapy.
Aging Cancer Research Development Program
Drs. Berger, Owusu, Philips
Dr. Nathan Berger, former division chief and dean of the medical school, is the PI on a major grant to examine aging and cancer in a program at CWRU and the Case Comprehensive Cancer Center. This program is multidisciplinary examining all aspects of the aging process and how it impacts on cancer biology, diagnosis, and response to therapy. Within the division of hematology and oncology, Dr. Cynthia Owusu is developing a geriatric oncology assessment program for older cancer patients as part of their overall evaluation for cancer care. Her initial efforts will be in breast cancer and GI oncology patients. Dr. Tanyanika Phillips-Lowe is developing a health equity program for thoracic oncology patients.
Research on Energetics and Cancer
Drs. Berger, Markowitz
Dr. Berger also is the PI on a center grant on transdisciplinary research on energetics (TREC) that is an intra-institutional program examining “energetics” on cancer and other events. Dr. Sandy Markowitz is an active participant in this program examining colonic prostaglandins.
Developmental Therapeutics and Investigator Initiated Clinical Trials Research
Drs. Dowlati, Baar, Barr, Brell, Cooney, Cooper, Gerson, Gibbons, Halmos, Kindwall-Keller, Krishnamurthi, Lazarus, Liu, Ma, Nock, Savvides, Silverman.
Dr. Afshin Dowlati is the Director of Developmental Therapeutics and the PI of the Institutional U01 grant for developmental therapeutics. A number of faculty are involved in clinical research with novel therapeutic agents conducted under the offices of NCI-CTEP Phase I and Phase II Clinical Trials Program for investigator-initiated clinical research and with support of the pharmaceutical industry for novel pharmaceutical agents. Dr. Smitha Krishnamurthy is the Co-Director of the Developmental Therapeutics office. Dr. Joanna Brell is the Chairman of the Protocol Review Committee. Drs. Joseph Gibbons, Henry Koon, Mary Laughlin, and Laura Moore are members of the Case Comprehensive Cancer Center IRB.
ICC Cancer Center clinical trial website 
