Hem Onc Research Hematologic Malignancies

Research laboratories in the Hematology and Oncology division continue to study regulatory mechanisms of blood cell development, the molecular mechanisms by which normal hematopoietic cells are transformed to leukemic cells, and the pathogenesis of stem cell transplantation-associated immune-mediated diseases. These studies have significantly advanced our understanding of hematological malignancies and may lead to improved therapeutics.

Dr. Marcos de Lima joined the faculty in September 2012 as section chief for Hematologic Malignancies and Stem Cell Transplantation in the Division of Hematology and Oncology, and Director of the Seidman Cancer Center Stem Cell Transplant Program. The goals for the hematologic malignancies and stem cell transplant (SCT) section for years 2013 and 2014 integrate clinical and research activities. The overall goals are as follows: 1- to increase allogeneic transplant availability for patients without matched donors; 2- relapse prevention after allogeneic transplants. Under goal #1, we will perform our first haploidentical allogeneic transplant under BMT-CTN protocol 1101, and have opened the Protocol Meso 1Z12 (PI Hillard Lazarus, study developed by M. de Lima and E. Shpall) a cord blood ex vivo expansion with mesenchymal precursor cells for hematopoietic recovery in patients with hematological malignancies. Other studies are detailed under individual investigators names in this report. Under goal #2, we have written and developed a study with Celgene (we are the national leaders), a phase I trial investigating oral azacitidine after allogeneic transplants (PI M. de Lima and B. William), and are developing a phase I study incorporating total marrow irradiation to enhance anti-tumor activity in the reduced intensity setting (PI P. Caimi and D. Mansur). The core of the clinical program is the support and development of investigator-initiated clinical trials in hematologic malignancies and SCT, as reviewed below.

Dr. Paolo Caimi’s research focuses on novel drug development in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Ongoing projects are investigating the strategy of whether inhibition of DNA repair can improve upon standard therapy in these lymphoproliferative disorders. He is conducting a phase I protocol CASE 2y10 entitled “Fludarabine and Methoxyamine for relapsed/refractory B cell malignancies”. Dr Caimi is also P.I. of a study developed in collaboration with Dr D. Wald investigating the use of lithium and ATRA as treatment for acute myelogenous leukemia. He is also supported by an NCI K12 training grant.

Dr. Erica Campagnaro leads the multiple myeloma program at UH Cleveland Medical Center. A former K12 Paul Calabresi Scholar, she is active in clinical care; medical education; and clinical and translational studies focusing on myeloma pathophysiology and treatment. She participates nationally in the field of myeloma as a member of the ECOG Myeloma Core Committee, and is site-principal investigator on the non-transplant ECOG myeloma therapeutic and laboratory corollary studies. Together with the ECOG Myeloma Core Committee, Dr. Campagnaro is investigating reasons for inferior survival in elderly myeloma patients compared to younger myeloma patients, and is principal investigator of a clinical trial of therapy for frail elderly myeloma patients in development.  She is also has a productive local collaboration in the field of myeloma with Dr. Frederic Reu, who leads the multiple myeloma program at the Cleveland Clinic Foundation. Together, they are performing clinical and translational investigation to address the need for more effective therapies in relapsed and refractory myeloma. In translational work, Dr. Hillard Lazarus, Dr. Campagnaro and Dr. Reu are studying the effects of a pro-apoptotic molecule on myeloma, and are working towards optimizing delivery of this treatment to myeloma cells by engineering multipotent adult progenitor cells to express the apoptotic molecule. In collaboration with Dr. Reu, they are conducting a Phase I/II Study of Lenalidomide and Azacitidine in Relapsed and Refractory Myeloma, which investigates the role of histone acetylation and deacetylation in the biology of myeloma growth and treatment, and whether combining the histone deacetylase inhibitor, azacitidine, with standard myeloma treatments, can improve outcomes in patients with relapsed/refractory myeloma and/ or help overcome resistance to standard myeloma treatments.

Dr. Brenda Cooper is exploring a variety of novel approaches to the treatment of acute myelogenous leukemia and serves as co-investigator on investigator-initiated institutional studies and pharmaceutical industry sponsored studies in our hematologic malignancies and blood and marrow transplant program. She is principal investigator on an institutional novel phase I/II trial (CASE 1908) combination of midostaurin (PKC inhibitor) with chemotherapy for high risk MDS and leukemia. Results of the phase I portion of this trial have been presented at the American Society of Clinical Oncology spring meeting this year. She is institutional investigator on a phase II randomized study of “ Epigenetic priming using Decitabine with Standard induction Chemotherapy in patients with Acute Myelogenous Leukemia” NYCC 1912 which is a protocol sponsored by our U01 Consortion and CTEP and  a phase III pharmaceutical sponsored study of vosaroxyn and cytarabine for relapsed AML. A pharmacodynamic study of decitabine and methoxyamine for untreated and relapsed AML is under development in collaboration with our translational core facility at the Seidman Cancer Center.

Dr. Stanton Gerson’s research is focused on understanding DNA damage repair in hematopoietic stem cell maintenance, aging, and leukemogenesis. Recent work in his laboratory has demonstrated critical roles of DNA repair proteins DNA-PK, Ku70, and MLH1 in hematopoietic stem cells. Stem cells deficient for DNA-PK or Ku70 lose quiescence and are compromised in self-renewal and repopulation. Further analyses have demonstrated that niche occupancy of these DNA repair deficient HSCs is severely impaired. He has also found a correlation of a loss of gene expression of DNA mismatch repair protein MLH1 and increased DNA microsatellite instability with age in humans. This age-related loss of DNA mismatch repair suggests mismatch repair pathway deficiency may contribute to the increased incidence of hematologic malignancies in older individuals. In addition, in an effort to improve the efficiency of hematopoietic stem cell transplantation for stem cell-mediated gene therapy, Dr. Gerson has developed an in vivo imaging system to directly visualize hematopoietic stem cell homing, expansion, and engraftment by expressing mutant DNA repair protein alkylguanine transferase (MGMT-P140K) in hematopoietic stem cells followed by selection with DNA damaging drugs. Dr. Gerson’s studies have significantly advanced our understanding of DNA repair in stem cell manitenance and have led to a clinical trial - Overexpression of the DNA repair protein O6 alkyguanine-DNA alkyltransferase in hematopoietic stem cells to protect bone marrow from DNA damaging chemotherapy.

Dr. Hillard Lazarus’ research focuses on clinical and translational initiatives in hematologic malignancies, hematopoietic progenitor cell transplantation and cellular therapies, and regenerative medicine efforts. Notable achievements in the past year include the demonstration in a Blood and Marrow Transplant Clinical Trials Network study that in vitro manipulation to remove effector cells from the donor allogeneic hematopoietic cell graft significantly lowered the likelihood of the recipient developing GVHD, but did not interfere with hematopoietic engraftment or likelihood of relapse. Dr. Lazarus and associates in the Eastern Cooperative Oncology Group reported the largest published experience of the therapy and outcome of prospectively treated adult ALL patients whose disease harbored the rare cytogenetic t(4;11) immunophenotype. Dr. Lazarus and the ECOG group also reported the results of the first integrative epigenomic study in adult B-cell ALL using the patient samples derived from the phase 3 ECOG trial E2993. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. They also identified novel clinically actionable biomarkers that provide the basis for a successor clinical trial using BCL-6 inhibitors for patients with the MLL gene rearrangement, a poor prognostic marker. Dr. Lazarus and Center for International Blood and Marrow Transplantation colleagues also reported an up-to-date summary of the significant improvements in autologous as well as allogeneic transplantation in hematologic malignancies over the past two decades. He also wrote and initiated a novel trial within the ECOG network in adult acute myeloid leukemia patients using eltrombopag, an orally administered thrombopoietin agent, designed to reduce or eliminate the need for platelet transfusions in the course of consolidation chemotherapy. Finally, Dr. Lazarus is the lead investigator for a national multi-center trial that is exploring suicide gene-transfection into the donor allogeneic graft that promptly will destroy donor effector cells mediating GVHD when the recipient is exposed to a small, “inert” molecule. Dr. Lazarus has continued to develop the use of highly innovative cellular therapies for regenerative medicine. He and his group recently completed the largest trial ever undertaken utilizing autologous bone marrow-derived ex vivo expanded mesenchymal stromal cells for the treatment of multiple sclerosis patients. This group also is developing novel cellular therapy protocols for tissue repair in macular degeneration, rheumatoid arthritis, asthma, and cystic fibrosis, as well as anti-cancer cellular therapies in plasma cell myeloma and malignant melanoma.

Research in Dr. CK Qu’s laboratory focuses on the cellular and molecular mechanisms by which protein and lipid phosphatases regulate hematopoietic cell development and leukemogenesis. His laboratory has demonstrated that protein tyrosine phosphatase SHP-2 (PTPN11) plays an overall positive role in hematopoiesis and that it promotes hematopoietic cytokine signaling in both catalytically-dependent and -independent manners. Dr. Qu and his group have also shown that gain-of-function mutations of PTPN11 identified in childhood leukemias cause these diseases by aberrant activation of hematopoietic stem cells and myeloid progenitors. In addition, his laboratory has demonstrated that PTPMT1, a newly identified mitochondria-based phospholipid phosphatase, plays a crucial role in hematopoietic stem cell self-renewal and differentiation. This study has also uncovered a heretofore unknown mitochondrial metabolic stress-induced checkpoint for hematopoietic stem cell differentiation, which helps better understand the pathogenesis of blood disorders associated with altered metabolism and oxidative stress. See Section 2. Cancer Cell Biology, above.

Dr. Basem William joined the faculty in mid-2012. His research focuses on clinical and translational approaches to treatment of hematological malignancies with special focus on stem cell transplantation. He is a principal investigator on a novel phase I/II trial of oral azacytidine maintenance after allogeneic transplantation in patients with MDS and AML. He is also collaborating with the University of Nebraska on a phase I/II trial for lenalidomide maintenance after autologous transplantation for NHL. He is working, with Dr Lazarus, on an analysis of genetic polymorphisms influencing cisplatin pharmacokinetics in patients who received autologous transplants and were conditioned with a cisplatin-based high dose regimen; in collaboration with University of West Virginia and on a retrospective analysis of influence of high dose regimen on outcomes of patients with NHL receiving autologous transplants collaborating with colleagues at the CIBMTR. He is also developing a novel clinical trial utilizing combination of curcumin and vitamin D in patients with early stage CLL.