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Pediatric Oncology Faculty Research

Robert Arceci, M.D., Ph.D.

Our laboratory is focused on the elucidation of fundamental mechanisms of cell growth, survival and senescence during normal and cancer development with the overall goal of identifying novel pathways for therapeutic targeting of leukemia and solid tumors leading to improved outcomes.The areas of current interest include: Epigenetic Mechanisms during Development, Cancer Pathogenesis and Senescence: Our interest in the molecular pathways contributing to leukemia cell survival and stem cell expansion resulted in the identification of a novel chromatin remodeling factor, which we termed PASG. Without PASG, mice develop abnormal genomic methylation patterns, defects in stem cell expansion, premature aging and increased leukemia predisposition. We have also identified a mutant form of PASG in a high percentage of leukemia samples that is associated with complex karyotypes, alterations in gene expression patterns, decreased genomic methylation and poor outcome in AML. We are currently pursuing these findings to better understand epigenetic patterning in leukemic stem cells as well as developing approaches to identify treatment approaches that induce replicative senescence in leukemia as well as understand basic mechanisms of aging.

Based in part on these studies, we have embarked on a large, integrative program, High Resolution Genomic and Epigenomic Mapping of High Risk Pediatric Sarcomas and Leukemias. This program is performing genome wide mutational, transcriptional and epigenetic analyses analysis of high pediatric sarcomas and acute myeloid leukemia. Using whole genomic microarray chips and next generation sequencing, we are now establishing the complete map of all RNA expression as well as a description of all genomic gains and losses. The overall goal of these studies is to create a detailed and comprehensive map of all the abnormal changes associated with high risk primary and metastatic sarcomas and AML subtypes. And while each of these critical areas is known to be altered in cancer, the integration of such detailed structural and functional data provides a unique opportunity for the discovery and development of therapeutic targeting of novel pathways in high risk cancers.  From the information obtained through these studies, we would then plan to perform rapid, high through-put screening of chemical and drug libraries in order to identify drugs that would potentially be more effective, more specific and less toxic therapies for these high risk leukemias that are so commonly resistant to conventional chemotherapy. This initiative has already provided novel analysis algorithms and integration of next generation sequencing data to identify distinctive RNA expression and epigenetic changes defining potentially key pathways in metastasis as well as mechanisms of resistance to chemotherapy of AML and modification of AML clonogenic stem cells.

Cancer Predisposition Syndromes: We identified the first human disease caused by loss of function of a large ribosomal protein. That disease, Diamond-Blackfan Anemia, is a bone marrow failure and cancer predisposition syndrome. This work was recently published as a Plenary Paper in Blood. We are now investigating how such molecular pathways produce the characteristics seen in patients in part through the generation of murine transgenic models, which should be useful in testing gene therapy approaches for treatment. Further, we are utilizing this model system to identify novel pathways for the treatment of hematological malignancies.

Our work has been funded in part by the NIH, DOD, NCI as well as through gifts from grateful families.

Patrick Brown, MD

Our laboratory has been busy developing new treatments for childhood leukemia that selectively target the leukemia cells and leave the childs normal cells relatively unharmed. These types of drugs are called molecularly targeted therapy, because they target abnormal genes and molecules that are present only in the leukemia cells. This type of treatment has the potential to represent a tremendous advance over standard chemotherapy, which is very non-specific and causes multiple severe side effects.

I am leading two national clinical trials that are the first to treat children with a new class of drugs called FLT3 inhibitors. These trials will tell us whether these drugs can improve the cure rates in very high risk forms of childhood leukemia. Our laboratory is testing samples from patients being treated on these trials to determine whether the drug is hitting its target (the FLT3 gene). We are also pursuing two other strategies for targeting childhood leukemia. One is using a new class of drugs called epigenetic modulators that can reverse abnormal gene expression patterns that cause and maintain some forms of childhood leukemia. The other is using a new class of drugs called CXCR4 antagonists that can enhance the effectiveness of anti-leukemia treatments by blocking survival signals provided to leukemia cells by the protective microenvironment in the bone marrow. We are hopeful that our work in these two areas can soon be translated into more new clinical trials that will lead to improved cure rates and less side effects for children with high risk forms of leukemia.

Our laboratory has been fortunate to receive support for this work through several sources, including the National Institute of Health, the Damon Runyon Cancer Research Foundation, the Leukemia and Lymphoma Society, the Childrens Cancer Foundation and the Gabrielles Angel Foundation.

Kenneth J. Cohen, MD, MBA

Dr. Cohen is the Director of Pediatric Neuro-Oncology and the Clinical Director in the Division of Pediatric Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. A principle focus of Dr. Cohen's research is the development and testing of novel therapeutic agents in children with brain tumors. Recent examples include the use of arsenic trioxide in the treatment of children with high-risk infiltrating astrocytomas. Results from this Phase 1 study will be utilized in the Phase 1 setting through the Children's Oncology Group. Other recently funded trials include cetuximab/irinotecan in the treatment of children with infiltrating astrocytomas and nimotuzumab in the treatment of children with diffuse pontine gliomas. A number of new therapeutic trials will begin this year including a trial of a novel hedgehog inhibitor for children with recurrent medulloblastoma, a comparison of erlotinib versus a standard chemotherapeutic in the treatment of recurrent ependymoma. A major component of Dr. Cohen's research now focuses on strategies to accelerate the introduction of novel therapeutics to children with high risk pediatric cancers. This research, funded by a major grant from the Solving Kids Cancer Foundation is focused on developing new models of collaboration between industry and academia that will allow for rapid movement of the most promising novel agents into children with cancer.

Alan Friedman, M.D.

Professor of Pediatric Oncology, conducts laboratory research investigating mechanisms that regulate formation of normal bone marrow cells and their transformation into acute myeloid leukemia (AML). In work published this past year in the scientific journal Blood, his group identified specific cell signals used by the hormones G-CSF or M-CSF to direct neutrophil or monocyte formation. This work is important as it may help improve use of G-CSF to stimulate the production of neutrophils to fight infections in patients receiving chemotherapy. In addition, the new signaling pathways Dr. Friedman has identified might be manipulated in leukemic cells to encourage their maturation to less harmful cells. During this past year, Dr. Friedman's group also conducted studies related to a protein termed RUNX1, which is mutated commonly in AML and which also regulates normal hematopoietic stem cell formation. His group identified chemical changes in this protein that controls its ability to increase the expression of target genes in the cell. Together with Dr. Elias Zambidis in Pediatric Oncology and Stephen Baylin in Adult Oncology, Dr. Friedman was awarded a seven year grant this past year by the National Institutes of Health to continue their collaborative research investigating mechanisms that allow RUNX1 and other proteins to control the formation of normal hematopoietic stem cells (HSC). This work is important both because leukemias often begin in the HSC and because the HSC is the cell that provides long-term engraftment after marrow or peripheral blood stem cell transplantation. Finally, together with Dr. Ido Paz-Priel in Pediatric Oncology, Dr. Friedman has found that C/EBPa or mutants of C/EBPa found in AML, inhibit cell death in cooperation with NF-kB. Their most recent efforts were published this past year in the Journal of Immunology and in Leukemia. Dr. Friedman is currently analyzing interaction between C/EBPa and NF-kB with the hope of developing a small molecule that blocks their interaction to induce death of leukemia cells and of other cancers that express these proteins.

Christopher Gamper, M.D., Ph.D.

My research seeks to identify factors critical to regulation of T cell effector function. T cells are an essential component of the adaptive immune response that specialize after activation to more efficiently target and destroy not only infected tissues but also tumor cells. Tumors are capable, however, of misdirecting the specialization of T cells and rendering them unresponsive. One mechanism that appears to contribute to this unresponsiveness is the permanent silencing of genes, including immune hormones called cytokines, by DNA methylation. Experiments designed to identify genes whose expression is increased in unresponsive T cells demonstrated that DNA Methyltransferase 3a (DNMT3a), which catalyzes addition of new methylation to DNA, is upregulated 38-fold in unresponsive cells. I generated mice that have T cells lacking DNMT3a and found that such T cells can specialize normally following activation to secrete particular cytokines but unlike normal T cells, DNMT3a deficient T cells can be redirected to secrete cytokines that are normally silenced because they fail to methylate the DNA of these cytokine genes. These findings suggest that use of drugs that block DNA methylation may be helpful to reawaken desirable anti-tumor cytokine gene expression if given together with a tumor vaccine. These findings were recently published in the Journal of Immunology.

A parallel project has identified that expression of a particular cytokine, interleukin-13, is regulated in T cells by Let-7 family micro RNA. Micro RNAs (miRNAs) are short RNA sequences that bind to messenger RNA (mRNA) and prevent translation of the mRNA into mature protein, thus blocking the function of a particular gene. After observing that some T cells make large amounts of IL-13 mRNA but little IL-13 protein, I inspected the IL-13 mRNA sequence and found a potential binding site for Let-7 miRNA. When this site was deleted from the IL-13 sequence the ability of Let-7 miRNA to block protein translation was destroyed. Furthermore, overexpression of Let-7 miRNA in an NKT cell line efficiently blocks secretion of IL-13 protein selectively. IL-13 is a hormone critical to allergic inflammation found in asthma, but also plays an important role in blocking anti-tumor immune responses in animal models of metastatic cancer. Thus increasing Let-7 miRNA levels to block IL-13 may impact a variety of allergic and anti-cancer treatments. This project, performed in collaboration with colleagues in Adult and Pediatric Hematology, has been submitted as abstracts to the upcoming American Association of Immunologists annual meeting held in Baltimore in May.

Bone marrow transplantation is an area where understanding the factors that promote and inhibit immune activation can have immediate clinical application. Blocking excessive immune activation, rendering the engrafted cells tolerant of the recipient, is critical to prevent graft versus host disease (GVHD), which can destroy normal organs with an intense autoimmune reaction. Such GVHD is useful to help destroy cancer cells but is unnecessary after BMT for non-cancerous conditions such as sickle cell anemia. Based on initial success using a modified BMT approach with immune-matched siblings of patients with sickle cell anemia, I have collaborated with colleagues at the National Institutes of Health to develop a follow-up trial to perform BMT using half-matched parent or sibling donors to treat sickle cell anemia. By using such half-matched donors, bone marrow transplantation to cure sickle cell anemia should become much more widely available.Blood samples from this trial will be utilized to test whether the mechanism for tolerance of the engrafted immune cells is due to generation of regulatory T cells that block excessive immune responses against the recipient's tissues. These samples will also be used to test a novel agent for effectiveness in blocking unwanted immune responses in vitro to determine if it is suitable to pursue for development as a drug to help block GVHD after transplantation.

Recent Publications

Gamper CJ, Agoston AT, Nelson WG, Powell JD. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol. 2009;183(4):2267-76.NIHMSID NIHMS168147.

Kathy Ruble, Ph.D.

Completed research for childhood cancer survivors at Johns Hopkins included an important study examining bone mineral density and body composition after bone marrow transplantation(BMT). Important finding from this study include new information on the risks of osteopenia/osteoporosis after BMT as well as the most appropriate way to screen survivors for this complication. In addition, this research revealed that BMT survivors are at risk for altered body composition that may compromise long term health outcomes. These results have been submitted for publication and will make important contributions to the state of the science in childhood cancer survivorship.

Grant funding is being sought for the next phase of this research where we plan to further investigate risks associated with altered body composition and pilot an exercise intervention to impact these risks. Kathy Ruble, the principle investigator, has received the Sigma Theta Tau, Founders Day Award and placed second in the New Investigator's Day, Johns Hopkins School of Nursing for her work on this study.

Heather Symons, M.D., M.H.S.

Dr. Symons research is in the area of novel immunotherapies for both hematologic and solid tumor malignancies. Her focus is on improving the efficacy, decreasing the toxicity, and improving availability of allogeneic lymphocytes. Towards this end, she is currently the principal investigator of a myeloablative haploidentical BMT trial for patients with refractory and/or relapsed high risk hematologic malignancies using T-cell replete grafts and post-transplantation cyclophosphamide. In the laboratory, she is investigating the role of the host immune system in combination with allogeneic donor lymphocytes in targeting and killing malignant cells. A recent publication showing the benefit of NK cell alloreactivity after haploidentical BMT has sparked new studies, both laboratory and clinical, on the use of natural killer cells to improve outcomes of pediatric cancers. Dr. Symons was awarded a K23 from the NCI in 2009. She is also the recipient of an Alexs Lemonade Stand Grant as well as a Hyundai Scholar Award.

Elias Zambidis, M.D., Ph.D.

Dr. Zambidis' lab is interested in the developmental biology of normal and malignant hematopoietic stem cells. He uses genetic manipulation and differentiation of both embryonic and adult pluripotent stem cells to study the cellular and molecular mechanisms of human hematopoiesis. Using human embryonic stem cells (hESC) derived from both normal and preimplantation genetic diagnosis (PGD)-screened embryos, as well as induced pluripotent stem cells (iPSC), he is exploring whether a human hemangioblast (bipotential progenitor of HSPC and endothelium) stem cell gives rise to the entire human hematopoietic system, and whether these cells can be derived and expanded from differentiating hESC. His laboratory is studying the role of a variety of proteins and signaling molecules that are critically important in orchestrating the initiation of human embryonic hematopoiesis by directing the formation of human hemangioblasts from hESC. hESC-derived blood progenitors are important not only for studies in human lympho-hematopoietic development and the understanding of the developmental origins of pediatric leukemia, but also possibly for clinical hematopoietic stem cell transplantation.


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