SCHOOL OF MEDICINE • DEPARTMENT OF MEDICINE

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 (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 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. 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.