Hematology/Oncology Research

Wolstein BuildingResearch Themes

The faculty in the hematology and oncology division has several research themes listed below.

Research themes and programs:

  1. Stem cell biology & therapeutics
  2. Apoptosis & autophagia
  3. Angiogensis & vascular medicine
  4. Colon cancer genetics
  5. Therapeutic signaling targets in thoracic oncology
  6. Research on energetics and cancer
  7. Aging cancer research development program
  8. Developmental therapeutics & investigator initiated clinical trials research

The Division of Hematology/Oncology has a strong basic, translational, and clinical research programs and funding to division members of over twenty-nine million (29) dollars of committed direct and indirect support. This level of funding consists of individual NIH grants, programmatic grants for the 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. It does not include funding of the P30 Case Comprehensive Cancer Center Grant, the institutional T32 Training Grants in medical oncology and hematology, and a K12 training grant in medical oncology.

Basic and Clinical Research Focus

The research programs of the Division are organized so it provides for a critical mass of investigators for collaborative research efforts and opportunities for growth development and recruitment including multiinvestigator grants such as, spores, PPG’s etc. Currently, no SPORES, PPGs exist within the division except for the Case Comprehensive Cancer Center P30 grant. Recruitment within the division is planned to embellish research depth and breadth already present in the group with the development of programmatic research. Each section will be divided in to basic and clinical research activities.

Stem Cell Biology, Hematologic Malignancy, and Therapeutics
Drs. Barr, Bunting, Cooke, Cooper, Gerson, Kindwall-Keller, Laughlin, Lazarus, Liu, Qu,
Salman

Basic Research:

These investigators study hematopoietic stem cells (HSC), umbilical cord blood stem cells (UCB), and mesenchymal stem cells (MSC). There are a number of collaborative projects by these investigators.

Dr. Bunting’s focus has been on leukemic signaling. He has two major areas of investigation. The first is novel non-myeloablative conditioning based on STAT5/PI3-K inhibition (Wang et al. Blood, 113, 2009). His laboratory has developed and optimized novel non-ablative conditioning based on inhibition of signal transducer and activator of transcription 5 (STAT5) and Grb2-associated binding protein-2 (Gab2)/phosphatidylinositol-3 kinase (PI-3K) signaling. They crossed STAT5ab+/null mice with Gab2-/-mice and found that the combined deficiency of STAT5 and Gab2 synergized to allow improved donor chimerism. This study is the first example of combinatorial signaling inhibition as a potentially less toxic and safer stem cell transplantation conditioning regimen. In mice containing floxed alleles of the STAT5a and STAT5b loci, conditional deletion of STAT5 using the interferon inducible Mx1-Cre allows for donor wild-type bone marrow cells injection to have a more efficient donor LT-HSC engraftment in primary and secondary hosts in the absence of any other form of ablative conditioning. A second research focus has been on targeting aberrant STAT5 activation in myeloid leukemias. Phosphorylated STAT5 is a biomarker associated with poor prognosis in certain types of myeloid malignancies including juvenile myelomonocytic leukemia and M4/M5 leukemias. Targeting of phosphorylated STAT5 or its aberrant signaling is difficult since direct inhibition of STAT5 transcriptional activity in its entirety presents significant side effects. Targeted STAT5 mediated PI3K/Akt/mTOR pathway activation in MPD shows therapeutic benefit with rapamycin. Dr. Bunting’s laboratory also recognized STAT5 controls bcl-2 expression in MPD through novel transcriptional and post-transcriptional mechanisms and demonstrated that this survival signal is critical for MPD progression.

Dr. Cooke is examining the immunologic mechanisms that contribute to the development of noninfectious lung injury following SCT. Investigations in his laboratory use mouse models of human disease to examine the hypothesis that the lung is a target organ of acute GVHD and is susceptible to two distinct, but inter-related pathways of immune-mediated injury. The first is fundamentally dependent upon the interactions of donor T cells and host antigen presenting cells and the generation of allo-antigen specific cellular effectors which home to the lung and cause damage and dysfunction. The second involves aspects of the innate immune response including donor accessory cells (macrophages and neutrophils) and the effects of inflammatory mediators like TNF and endogenous endotoxin as they interact via a “gut-liver-lung” axis of inflammation. These findings are significant because they support a paradigm shift away from identifying lung injury after SCT solely as an idiopathic clinical syndrome and toward understanding idiopathic pulmonary syndrome (IPS) as a process in which the lung is a target of two distinct, but inter-related pathways of immune mediated injury. Although a significant body of data supports a role for both lymphoid and myeloid cellular effectors in the development of IPS, the mechanisms by which donor leukocytes traffic to the lung and other GVHD target organs are still poorly defined. Currently, his laboratory is determining the role of endovascular injury and activation, chemokines and adhesion molecules in this context.

Dr. Gerson’s laboratory focuses on stem cell aging due to acquired defects in DNA repair. His research is studying mouse models and human stem cells from normal individuals to define the role of DNA repair in stem cell maintenance. His studies identify a number of DNA repair processes that are essential for normal stem cell function. Dr. Gerson is the PI on the institutional the grant for the Center of Stem Cells & Regenerative Medicine, the National Center for Regenerative Medicine (NCRM), and a capital equipment grant associated with NCRM.

Dr. Laughlin’s laboratory is focusing on 3 lines of inquiry:

  1. Gene regulation in cell-cell interactions occurring between normal hematopoietic stem cells and bone marrow stromal and vascular endothelial cells with focus on transcription factor regulation in pathophysiology underlying T-cell leukemogenesis.
  2. Immunobiology of human neonatal vs. adult CD4+ T-cells, with specific emphasis on transcription factor regulation including NFAT1, FoxP3, AP-1, and Bach2. 3) Cell-cell interactions between marrowderived hematopoietic stem cells with endothelial cells and pericytes in the process of vasculogenesis in response to ischemia.

Dr. Qu is examining SHP-2 inhibitors as potential therapeutic agents for JMML and Noonan Syndrome. In the last year research his laboratory focused on 3 major projects:

  1. The molecular mechanisms by which gain-of-function disease mutations in SHP-2 tyrosine phosphatase induce hematological malignancies.
  2. the identification of small molecular weight compounds that selectively inhibit SHP-2 activity and
  3. the characterization of roles of novel phosphatases MIP and PTPMT1 in physiology. These studies have led to several publications including one publication on the “Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca2+ homeostasis" in Nature Cell Biology, 2009, 11:769-776 that was featured in the Press Release for Nature and Nature research journals, May 24, 2009 to highlight the importance of our findings.

New Programs: It is planned that in the next year, Drs. Gerson, Bunting, Qu, and Yang from Biochemistry will submit a PPG on leukemia. Dr. Laughlin is organizing an inter-institutional PPG in Core Blood transplantation questions.

Clinical Research:

Dr. Barr’s research focuses on novel drug development in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Two ongoing projects are investigating the strategy of whether inhibition of DNA repair can improve upon standard therapy in these lymphoproliferative disorders. First, a Phase I trial of methoxyamine in combination with fludarabine in patients with relapsed or refractory hematologic malignancies. A separate cohort of CLL patients will be studied to evaluate the disease specific toxicities with this combination. Correlative studies are being done to further investigate the in vivo mechanism of action of methoxyamine as well as to identify the biologically optimal dose for further study. Secondly, a multi-center Phase II trial of fludarabine, bortezomib and rituximab is being performed in patients with relapsed follicular lymphoma. This trial is being built on Dr. Barr’s own Phase I results using this regimen in various indolent NHL subtypes and being coordinated by the Hoosier Oncology Group. Correlative studies as part of this study will determine if bortezomib is able to inhibit repair of the fludarabine induced DNA lesion.

Dr. Cooke’s basic laboratory insights are being actively translated back to the clinical setting. In pilot studies he showed the TNF antagonists are saluatory for idiopathic pulmonary syndrome. Currently, he has developed a national multi-center trial that using a TNF antagonist for IPS.

Dr. Cooper has focused her recent research on the development of safe and novel therapeutics for elderly patients with acute myelogenous leukemia. Her studies show that elderly patients suffered no more toxicities than their younger counterparts. She opened an investigator-initiated clinical trial entitled “A Phase I/II clinical trial of Midostaurin and Azacitidine for elderly patients with acute myelogenous leukemia and advanced myelodysplastic syndromes” as of August 2009. A Phase I study of methoxyamine and decitabine is now being developed for the relapsed/refractory AML population as part of an R01 grant entitled “methoxyamine in malignant diseases” (PI, Stanton Gerson).

Dr. Kindwall-Keller is the Principal Investigator on a one versus two unit non-myeloablative umbilical cord blood stem cell transplant trial, “A Pilot Study of Multiple Umbilical Cord Blood Unit Transplantation Following Non-Myeloablative Conditioning in Patients with Hematologic Disorders”. This trial has enrolled over 50 patients. She serves as co-principal investigator for the CIBMTR myeloablative double unit umbilical cord blood trial (05-DCB). She is the co-investigator on two investigator initiated clinical trials, “A Phase I Trial of Bendamustine Plus Alemtuzumab for the Treatment of Fludarabine Refractory Chronic Lymphocytic Leukemia” and “A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for Myelodysplastic Syndrome”, as well as the site principal investigator on five pharmaceutical sponsored trials. Additionally, she will be the co-principal investigator on the lenalidomide, dexamethasone, azacitidine investigator-initiated Phase I clinical trial for multiple myeloma.

Dr. Lazarus is the Principal Investigator of the Case Consortium, Blood & Marrow Transplant Clinical Trials Network (BMT CTN), Chair, Blood & Marrow Transplant Sub-Committee, Eastern Cooperative Oncology Group (ECOG), the Director of the Hematopoietic Stem Cell Processing Laboratory, and the Co-Chair, Stem Cell and Hematologic Malignancy Program, Comprehensive Cancer Center Case Western Reserve University. His research focuses on clinical and translational initiatives as they relate to hematologic malignancies, hematopoietic stem cell transplantation and cellular therapies. Notable achievements in the past year included the observation that for the first time, use of higher doses of anthracyclines during induction chemotherapy results in statistically significant improvement in patient overall survival (see Fernandez et al, NEJM 2009, in press September 24, 2009, see Bibliography list). In an additional cooperative group study he showed the superiority of allogeneic hematopoietic stem cell transplantation over conventional chemotherapy in adult acute lymphoblastic leukemia, Philadelphia chromosome positive disease (Fielding et al, Blood, 2009). Additionally, he and his co-workers demonstrated that longer total transport times from collection to infusion of unrelated donor grafts adversely impacted upon patient outcome (Lazarus et al, Biol Blood Marrow Transplant, 2009). Presently, he is continuing his involvement in the study of new and novel anti-cancer agents, improved methods of examining hematopoietic progenitor content in grafts, use of mesenchymal stem cells and multi-potent adult progenitor cells for the treatment of graft-versus-host disease, double as compared to single umbilical cord blood grafts for transplant, and the implementation of new strategies to reduce relapse after hematopoietic stem cell transplantation.

Apoptosis & Autophgia
Drs. Distelhorst, Matsuyama
Basic Research

Dr. Distelhorst’s laboratory investigates basic mechanisms of cell death regulation. This includes apoptosis and autophagy, and the regulation of these processes by calcium signals and by the Bcl-2 protein family. The lab has made many novel discoveries, including the important role of Bcl-2 in regulating calcium signals through interaction with the IP3 receptor calcium channel, the enhancement of ABT-737 induced apoptosis by an IP3 receptor derived peptide that dissociates the Bcl-2 protein from the IP3 receptor, the induction of autophagy in lymphoma cells by the glucocorticoid hormone dexamethasone, and the role of micro RNA repression by dexamethasone in mediating Bim upregulation and apoptosis in lymphoma cells.

Dr. Matsuyama investigates the molecular mechanism of programmed cell death. He is elucidating how Bcl-2 family proteins determine the cellular fate to survive or die. Bcl-2 family proteins are evolutionary conserved proteins regulating cell death. Bcl-2 acts as an anti-apoptotic protein and Bax as a proapoptotic protein. He found that Ku70 binds and inhibits Bax in the cytosol, and this activity is independent from previously known function of Ku70 as a DNA repair protein in the nucleus. He also reported that Hdm2 (human double minute 2) is an ubiquitin ligase of Ku70. His work provides a model explaining how DNA damage induces Bax-mediated cell death through decreasing Ku70 levels in the cell. He disocivered how interferone receptor 2 (IFNR2) has previously unidentified function as a Bax inhibitor. His laboratory found that the cytoplasmic domain of IFNR2 is cleaved from the receptor (probably by membrane associated protease) and localizes in the cytosol as an anti-Bax peptide. Importantly, his laboratory found that malignant prostate cancer cells express extremely high levels of the anti-Bax peptide derived from IFNR2, suggesting that this peptide confers cancer cells resistance to Bax-mediated apoptosis. Since Bax is a key mediator of apoptosis induced by chemo- and radiationtherapies, the discovery of anti-Bax activity of IFNR2 provides a new model of how cancer cells acquire resistance to anti-cancer therapies. Thus, his work shows that Bcl-2 is an oncogene that confers cancer cells resistant to apoptosis.

Angiogenesis, Vascular Medicine, Thrombosis and Therapeutics
Drs. McCrae, Nieman, Schmaier
Basic Research

Dr. McCrae studies antiphospholipid antibodies and angiogenesis. His work over the current year includes on translational studies concerning antiphospholipid antibody mechanisms, and characterizing the kininogen deficient mouse prepared by his lab.

Dr. Nieman’s research program focuses on the interaction between the thrombin receptors, PAR1 and PAR4, on the surface of platelets. Using bioluminescence resonance energy transfer (BRET), he has demonstrated PAR1 and PAR4 heterodimers and is mapping the interface of these two proteins. Dr. Neiman has recognized and characterized a novel region on PAR4 that optimizes its activation by thrombin. An antibody to this region blocks human and murine thrombin-induced platelet aggregation. PAR4 is a suitable target for anti-platelet therapy because it is expressed on platelets and relatively low abundance elsewhere. Blocking PAR4 may be a more specific target than targeting PAR1, which has more potential side effects due to PAR1’s wide tissue distribution.

Dr. Schmaier’s laboratory is investigating novel mechanisms for arterial thrombosis. Dr. Schmaier several mouse knockout models (prolylcarboxypeptidase hypomorph, angiotensin receptor 2 KO, bradykinin B2 receptor KO, angiotensiongen heterozygous, factor XII KO) influence arterial thrombosis risk without influencing hemostasis. Dr. Schmaier has recognized that changes in vessel and/or organ reactive oxygen species influence arterial thrombosis risk. Elevation of vessel and organ ROS result in a prothrombotic animal in the prolylcarboxypeptidase hypomorph; reduction of ROS results in thrombosis protection in the bradykinin B2 receptor knockout. His laboratory is also developing a novel oral direct thrombin inhibitor called “Thrombostatin” derived from the angiotensin converting enzyme breakdown product of bradykinin. The lead compound FM19 is orally active and reduces arterial thrombosis risk and prostate cancer growth in murine models when added at > 5 mg/ml to the drinking water. Last, Dr. Schmaier’s laboratory is examing the mechanism and role of factor XII in post-natal angiogenesis. The factor XII knockout animals, constitutively and after wounding, have reduced vessel growth in skin. New Programs. Drs. Schmaier and McCrae have been working with Drs. Jain and Simon in cardiology to prepare and submit a vascular medicine and thrombosis PPG in the next year.

Clinical Research

Dr. McCrae is the institutional PI on a national NHLBI transfusion medicine protocol for rituxan in patients with antibodies in congenital hemophilia.

Colon Cancer Genetics and GI Malignancies
Drs. Krishnamurthy, Markowitz, Meropol
Basic Research

Dr. Markowitz leads a multidisciplinary team of investigators in comprehensive studies of colon cancer etiology prevention and treatment. The Markowitz laboratory research program continues to focus on translational studies of human colon cancer. Current investigative work includes:

  1. continued improvements and clinical applications of testing for methylated DNA in stools for early detection of colon cancer;
  2. the development of new technology for detecting methylated DNA leading to first blood test for early detection of colon cancer by detecting aberrantly methylated DNA in serum;
  3. the continued discoveries regarding the role of the 15-PGDH tumor suppressor pathway in colon cancer. The Markowitz laboratory recently reported that humans with low colonic levels of this endogenous NSAID like gene are clinically resistant to the colon tumor preventive activity of Celecxoib;
  4. the discovery of the first germline mutations in the GALNT12 glycosyl-transferase gene, and the demonstration that these mutations are associated with late development of human colon cancer.

New Programs. Dr. Markowitz is leading an inter-departmental GI SPORE working group targeting submission of a Case GI SPORE in September, 2009.

Clinical Research

Dr. Krishnamurthi is the PI on the following open clinical trials in the ICC and CCCC.

  1. CASE 2204 A Phase IB Study in Patients with Metastatic Colorectal Cancer to Evaluate Pharmacodynamic Effects of Erlotinib in Combination with Modified FOLFOX6 (mFOLFOX6) and Bevacizumab.
  2. CASE 1205 (P.I.): Dose-Dense and Dose-Intense Alternating Irinotecan/Capecitabine and Oxaliplatin/Capecitabine: Phase I in Solid Tumors and Phase II with Bevacizumab as First-Line Therapy of Advanced Colorectal Cancer. This study is sponsored by the National Cancer Institute.
  3. CASE 3206 A Phase I Study of Sunitinib Malate and Standard Infusion Gemcitabine in Solid Tumors. This study is sponsored by the National Cancer Institute.
  4. MRK 1Y08 A Phase I Investigation of MK-5108 in Patients with Advanced Solid Tumors. This study is sponsored by Merck and evaluates an investigational compound, MK-5108, an aurora kinase inhibitor.
  5. BRMY 1206 A Pharmacokinetic Study of BMS-582664 in Subjects with Advanced Solid Tumor Malignancies and Normal Hepatic Function or Hepatocellular Carcinoma with Impaired Hepatic Function (Sponsored by Bristol Myers).
  6. She will be the co-PI of CASE 2208 (Richard Kim Lead PI at Cleveland Clinic). A Phase I/II, Open-Label Study to Determine the Maximum Tolerated Dose (MTD) of the Combination of CC-4047 and Cetuximab, and to Evaluate the Efficacy of this Combination in Subjects with Metastatic Colorectal Carcinoma, which will open at the Cleveland Clinic in 9/09, then at the Ireland Cancer Center.

Dr. Meropol joined the Division of Hematology and Oncology in July, 2009. His clinical trial research pursues trials in patients with colorectal cancer. He is currently Chair of a national study for patients with metastatic colorectal cancer. This trial tests the hypothesis that thymidylate synthase confers resistance to treatment with 5-fluorouracil. This is the first national trial in patients with metastatic colorectal cancer that assigns treatment based upon a molecular classifier. He is Chair of the NCI Colon Cancer Task Force is involved in the development and monitoring of all Phase III and large Phase II publicly-funded studies. In his role as Chair of the Developmental Therapeutics Committee in ECOG, he is involved in the conduct of a variety of correlative studies aimed at improving individualization of cancer therapy through identification of both pharmacogenetic (germline) and pharmacogenomic (somatic) predictive classifiers. Dr. Meropol is also PI of 3 R01 grants that support studies of cancer patient decision making.

Drs. Dowlati, Koon, Ma
Basic Research

Dr. Dowlati’s research focuses on 2 main themes. First is the area of phase I drug development of novel anticancer agents. Amongst these include first-in-human studies of anti-angiogenic agents and signal
transduction inhibitors. His laboratory also focuses on the correlative studies to determine pharmacodyanmic effects of these agents. His laboratory examines targeting the STAT3 pathway in lung
cancer.

Dr. Koon is examining ALK tyrosine kinase signal transduction in cancer. His laboratory is currently trying to determine what are ALK’s downstream PI3K-dependent targets.

Dr. Ma studies the role of MET receptor kinase in lung cancer biology and its targeted inhibition using small molecule inhibitors and monoclonal antibody. He has previously defined the expression, mutations and functions of MET and mutant MET in lung cancer. He has also been investigating the cross-talk of MET signaling with the ERBB family receptors including EGFR/ERBB1. Recently, his laboratory demonstrated with both in vitro and in vivo evidence that combined MET and ERBB inhibition using SU11274 and erlotinib overcomes the EGFR inhibitor resistance mediated by the T790M-EGFR resistant mutation. In collaboration with Dr. Yanming Wang in Department of Radiology, and Division of Radiopharmaceuticals, he has developed a C11-labeled SU11274 using a radiosynthetic approach as a novel in vivo molecular imaging agent for assaying MET receptor expression using microPET/MRI. Development of in vivo molecular target imaging agents such as [C-11]SU11274 provides an extremely novel, non-invasive platform for imaging MET-targeting inhibitors in clinical trial studies.

Clinical Research

Dr. Ma is the principal investigator on two early phase clinical trials using MET-targeting agents. In one study, XL184 (Exelixis), a multitargeted inhibitor against MET and RET/VEGFR, is used in combination with erlotinib in a phase 1/2 study in advanced NSCLC patients with secondary resistance to the EGFR inhibitor erlotinib. The second trial involves the one-arm antagonistic monoclonal antibody against MET receptor, MetMAb (Genentech), in combination with erlotinib in a phase 2 study in advanced NSCLC patients.

Geriatric Oncology and Health Care Equities Programs
Drs. Berger, Owusu, Philips
Clinical Research

Dr. Berger 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. His goal is to develop an interdisciplinary research initiative within the Comprehensive Cancer Center that will integrate aging and cancer research with the goal of being recognized as a formal Aging-Cancer "Program", with a stable base of peer-reviewed funding, including a funded training program, by the time of the CCSG renewal, 08/01/06. This program" development is being accomplished by leveraging the considerable resources and expertise of cancer researchers and aging researchers associated with the NCI-funded Comprehensive Cancer Center, the NIA-funded Memory and Aging Center, and the VAMC-funded Geriatric Research, Education and Clinical Center (GRECC). This initiative will leverages Center-associated and non-associated researchers and educators from across CWRU including the Schools of Medicine, Nursing, Arts & Sciences, and Social Services, strategically employing development funds to support faculty recruitment, pilot project expansion, and development of shared resources. The "Program" will develop enhanced Aging-Cancer research studies in the priority areas of treatment, efficacy and tolerance; effects of comorbidity; and the biology of aging and cancer.

Dr. Owusu is the leader of the clinical geriatric oncology program in the division of hematology and oncology. Her research focuses on older women with breast cancer with the overarching goal to reduce age-related cancer health disparities by increasing the number of older cancer patients who receive standard of care treatment and are eligible for cutting edge research. This entails developing therapeutic clinical trials for the “fit older cancer patient” and intervention clinical trials for the “not so fit elderly patients” to reverse adverse outcomes and optimize oncology care in this vulnerable patient population. She developed an investigator-initiated trial “Safety and Efficacy of Single Agent Trastuzumab in Older women with Early-stage Her2 Positive Breast Cancer: A Phase II Trial”. This trial is a single arm open label trial of 124 patients involving seven institutions nationwide with the objective of evaluating threeyear cumulative incidence of cardiac events. Secondary objectives include three-year disease-free and overall survival, longitudinal geriatric assessments, physiologic cardiac markers for cardiac monitoring and long-term cardiac monitoring to evaluate the sequelae of trastuzumab-induced cardiotoxicity. Additionally, she is running a pilot study entitled “The Vulnerable Elders Survey Study of Older Breast and Colon Cancer Patients”. This investigation is a prospective cohort study designed to determine the utility of the Vulnerable Elders Survey as a screening tool for identifying older breast and colon cancer patient at increased risk of functional decline and mortality and in need of a comprehensive geriatric assessment.

Dr. Phillips is the leader of the clinical health care equities program of the division of hematology and oncology. Her current research includes understanding patient preferences for care at the early phase of treatment in end stage lung cancer. She is also examining factors that influence full information exchange at the early phase of treatment in lung cancer in vulnerable populations. Last, she is studying variations in care practices and patient outcomes at the early phase of treatment in vulnerable populations.

New Programs. Drs. Berger and Schmaier are co-PIs on pending U01-RFA-AG-09-003 to examine mechanism and therapies for anemia in elderly patients. This program at CWRU-UHCMC is one of several academic institutions (Hopkins, Duke, Utah, Chicago, Stanford, Howard, UCLA and CWRU) in the nation participating in the translational research program. CWRU will serve as the Hematopoietic Stem Cell Tissue Core Repository for the entire consortium.

Research on Energetics and Cancer
Drs. Berger, Markowitz

Dr. Berger is the PI on a center grant on transdisciplinary research on energetics (TREC) that is an intrainstitutional program examining “energetics” on cancer and other events. Dr. Sandy Markowitz in the division is an active participant in this program examining colonic prostaglandins. The goals of this program are defined organizationally and scientifically. Organizationally, he seeks 1) to establish a productive, durable program for transdisciplinary research on energetics and cancer at Case University, 2) to provide pilot project support and training opportunities for new and established scientists who can conduct integrative research on energetics, energy balance and their consequences relative to cancer across the continuum-- from cancer causation and prevention through survival, and 3) to establish collaborative relations with investigators throughout our university and at other TREC Centers and universities to maximally and synergistically utilize resources to significantly impact problems associated with obesity and cancer. Scientifically, the program conducts a spectrum of mechanism-based laboratory, clinical and population-based studies to identify targets for prevention and control of obesity and interruption of the linkage between obesity and cancer. The scientific aims are defined by three programs and two pilot projects which are highly interactive and are supported by three TREC core facilities and by the 17 Comprehensive Cancer Center core facilities. Project 1 seeks to determine the intestinal tumor-inducing effect and molecular signaling pathways associated with high-fat diet versus obesity in unique strains of mice with chromosomal substitutions rendering them susceptible or resistant to the obesigenic effects of high-fat diets. Project 2 will examine candidate gene variance and haplotype, associated biomarkers, and insulin-resistance syndrome related serum markers to understand how insulin-resistance syndrome, related genes and dietary factors work in concert in the etiology of human colon neoplasia. Project 3 will investigate determinants of obesity and metabolic dysfunction during the critical life-transition period of adolescence. This study will capitalize on an unique population cohort followed as part of the Cleveland Children’s Sleep and Health Study and will investigate sleep phenotype and sleep disturbances as a novel and important determinant of obesity and its relation to metabolic dysfunction.

Developmental Therapeutics and Investigator Initiated Clinical Trials Research
Drs. Dowlati, Gerson, Liu, Cooney, Krishnamurthy, Gibbons, Baar, Silverman, Savvides

Dr. Dowlati is head of the Developmental Therapeutics programs and the PI of the institutional 5U01 award on “Phase I Trials of Anticancer Agents”. Dr. Krishnamurthy is an Assistant Leader of the clinical trials office in the ICC.

Dr. Baar is the PI of three active protocols in breast cancer: 1) 3 P30 CA043703-19S2 (9/16/08 – 3/31/09), Avon-NCI Progress for Patients Award, MUC1 Peptide and poly-ICLC Vaccine for Triple- Negative Breast Cancer. 2) Novartis Pharmaceuticals (1/1/09 – 12/31/11), A Phase I Study of Dose-Escalated LBH589 + Fulvestrant for ER(+) Metastatic Breast Cancer. 3) Genentech (1/1/09 – 12/31/1), Docetaxel, Carboplatin, Trastuzumab and Bevacizumab (TCH+B) for Early-Stage HER-2/neu (+) Breast Cancer and Bone Marrow Micrometastases

Dr. Cooney is involved in a number of clinical research activities related to GU malignancy. His investigator-initiated trials are as follows:

  1. CASE 2Y04. Phase I Trial of Daily CC-5013 (Revlimid) and
    Docetaxel Given Every Three Weeks (Principal Investigator);
  2. CASE 5Y05. A Phase I Study of Bevacizumab in Combination with SU11248 (Site Principal Investigator);
  3. CASE 12805. Phase II Trial to Assess the Activity of Ketoconazole Plus Lenalidomide in Patients with Prostate Cancer Progressive After Androgen Deprivation (Site Principal Investigator);
  4. CASE 4Y06. A Phase I, Open-Label Study to Determine the Maximum Tolerated Dose (MTD) and to Evaluate the Safety Profile of CC-4047 in Subjects with Advanced Solid Tumors (Principal Investigator).

His cooperative groups trials where he is the institutional PI are:

  1. ECOG 2805. A Randomized, Double Blind Phase III Trial of Adjuvant Sunitinib versus Sorafenib versus Placebo in Patients with Resected Renal Cell Carcinoma (Site Principal Investigator); and
  2. ECOG 3805. CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (Site Principal Investigator).

Dr. Cooney has several industry-sponsored trials where he is the site PI:

  1. PFIZ 12805. A Phase II, Randomized, Non- Comparative, Two Arm Open Label, Multiple Center Study of CP-751,871 in Combination with Docetaxel and Prednisone in Chemotherapy-Naïve (Arm A) and Docetaxel/Prednisone Refractory (Arm B) Patients with Hormone Insensitive Prostate Cancer (Site Principal Investigator);
  2. SANO 3806. A Randomized, Open Label Multi-Center Study of XRP6258 at 25 mg/m2 in Combination with Prednisone Every 3 Weeks Compared to Mitoxantrone in Combination with Prednisone for the Treatment of Hormone Refractory Metastatic Prostate Cancer Previously Treated with a Taxotere - Containing Regimen (Site Principal Investigator);
  3. EORTC 62072. Randomized Double Blind Phase III Trial on Pazopanib versus Placebo in Patients with Soft Tissue Sarcoma whose Disease has Progressed During or Following Prior Therapy (Site Principal Investigator);
  4. PFIZ 1808. Axitinib (AG-013736) as Second Line Therapy for Metastatic Renal Cell Cancer: Axis Trial (Site Principal Investigator); 5) PFIZ 2808. A Multicenter, Randomized, Double-Blind, Phase III Study of Sunitinib Plus Prednisone versus Prednisone in Patients with Progressive Metastatic Hormone-Refractory Prostate Cancer after Failure of a Docetaxel-Based Chemotherapy Regimen (Site Principal Investigator), and 6) GLAX 2808. A Study of Pazopanib versus Sunitinib in the Treatment of Subjects with Locally Advanced and/or Metastatic Renal Cell Carcinoma (Site Principal Investigator).

Dr. Dowlati has a number of active clinical trials. He has two on-going Phase I trials: A Phase I, Open-Label, Study of the Safety, Tolerability, and Pharmacokinetics of Pazopanib in Combination with Paclitaxel on a Weekly Schedule for Three Consecutive Weeks of a 28-Day Cycle and with Paclitaxel and Carboplatin on an Every 21 Days Schedule and An Open-Label and a Phase Ib Study to Assess the Long Term Safety Profile of Pazopanib in Cancer Patients. Dr. Dowlati also is the PI on a number of investigator-initiated Phase I studies and several Phase II and III grants: A Phase II Study of XL647 in Subjects with Non-Small-Cell Lung Cancer; A Randomized, Double Blind Phase II Study of Erlotinib with or without SU011248 in the Treatment of Metastatic Non-Small Cell Lung Cancer; A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase III Study of Single-agent Tarceva (Erlotinib) Following Complete Tumor Resection with or without Adjuvant Chemotherapy in Patients with Stage IBIIIA Non-small Cell Lung Carcinoma who have EGFR-positive Tumors, and A Randomized, Double Blind Phase II Study of Erlotinib with or without SU011248 in the Treatment of Metastatic Non-Small Cell Lung Cancer.

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. Gerson In collaboration with Drs Liu, Barr, Koon and B Cooper have developed a new drug and have patented its application in cancer chemotherapeutics. The drug is methoxyamine and the target is Base Excision Repair. They are now bridging the translational preclinical efficacy models in the lab with the development of combination chemotherapy in cancer patients. Two ongoing Phase 1 clinical trials are underway. The clinical disease targets are lung cancer, melanoma, MDS, myeloma and CLL.Dr. Savvides is the principal investigator of a first in man study Phase I study of methoxyamine and temozolomide in patients with Solid Tumors (CASE 1Y05). He is also the PI of a Phase II NCI (CTEP) sponsored trial of BAY 43-9006 in patients with advanced anaplastic carcinoma of the thyroid (CASE 5304).

Dr. Savvides directs a multiple physician-initiated phase II clinical trials for patients with locally advanced or recurrent/metastatic head and neck cancer. He is also the study co-chair on a national Phase III randomized trial in ECOG E 1305 of chemotherapy with or without bevacizumab in patients with recurrent or metastatic head and neck cancer.

Dr. Silverman is the PI of several protocols: 1) 6/06-Present: Washington University HRPO 04-1312: A Phase 2 randomized study of physiologic (6 mg daily ) and high dose (30mg daily) estradiol in the treatment of estrogen receptor positive metastatic breast cancer. 2) 08/07-Present: GlaxoSmithKline: A randomized, double-blind multicenter, placebo controlled study of adjuvant lapatinib in women with early stage erbB2 over-expressing breast cancer. Est TDC $60,000. 3) 11/08-Present: Hoosier Oncology Group: Phase II Study of Combined VEGF Inhibitor (Bevacizumab + Sorafenib) in Patients with Metastatic Breast Cancer. Est TDC $4000.

As noted above, Dr. Meropol holds 3 R01 grants for studies of patient decision making. A theme in this work is understanding the decision making process regarding clinical trials, and developing methods to overcome barriers to participation.

The clinical research activity in the division of hematology and oncology in the ICC is a robust one. In the period from January 1, 2008 through August 22, 2009, there were 610 patients entered on active clinical trials in the entire University Hospitals Health System operation. The largest number of patients were enrolled at UHCMC (460) followed by LIUCC (53), UH-Westlake (36), and UH-Chagrin Highlands (32). Out of the 610 patients enrolled in the UHHS, 392 or 64% were enrolled by physicians in the hematology and oncology division. The top ten patient enrolling physicians in CCCC therapeutic clinical trials in the division of hematology and oncology were, in decreasing order, Silverman (57), Savvides (30), B. Cooper (30), Bokar (27), Saltzman (26), Lazarus (23), Cooney (21), Nock (19), Kindwall-Keller (18), Dowlati (15).