Program Leader: E. Eklund, MD
Program Co-Leader: Leo Gordon, MD |
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The Hematologic Malignancies Program of the Robert H. Lurie Comprehensive Cancer Center combines nationally recognized investigators in clinical research with investigators with expertise in basic sciences and translational research. The major research themes within the program are in the areas of novel therapeutics and molecular mechanism of hematologic disease. Program members have made significant contributions in the areas of molecular leukemogenesis, biologic therapies, hematopoiesis, ex vivo stem cell expansion, and allogeneic hematopoietic stem cell transplantation. Clinical trials have been or are being conducted with novel purine analogs, retinoids, monoclonal antibodies, recombinant toxins, radioimmunotherapy, chemoimmunoconjugates, anti-idiotype vaccines, anti-bcl-2 constructs, proteosome inhibitors, arsenic trioxide, stem cell transplantation, and adoptive immunotherapy. This multidisciplinary interdepartmental program has 30 members from 11 departments in 3 schools. Between January, 2001 and September, 2006 there have been 331 publications from the current program members. Ninety-Two (28%) of these publications represent intra-programmatic collaborations and 101 (30%) represent inter-programmatic collaborations. Total current cancer relevant peer reviewed funding for the Hematologic Malignancies Program is $4,188,955 (direct) with $2,101,336 (direct) from NCI, and $2,087,619 (direct) from other peer reviewed sources. The Cancer Center provides the resources that are necessary to ensure success of the program.
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The members of the Hematologic Malignancies Program have made significant contributions to understanding the pathogenesis of malignant hematologic disease, many of which are being extended into testing of novel therapeutic compounds to target these abnormalities.
The Program has an active group involved in identifying molecular defects in myeloid leukemias. The laboratory of Dr. Leonidas Platanias has a major focus on disruption in signaling pathways in malignant myeloid cells. Their studies have lead to important insights into abnormalities in signal transduction pathways activated by interferon and retinoic acid receptors. These abnormalities involve PKC, p38 MAPK and mTOR, which are all rationale therapeutic targets. The laboratories of Drs. Nabeel Yaseen and Dr. Elizabeth Eklund have been identifying target genes for Hox proteins and leukemia associated Hox-fusion proteins. These studies are designed to better understand Hox code function in normal and malignant myelopoiesis. Identification of Hox target genes may suggest rational targets for therapeutic interventions in myeloid leukemia. Drs. Platanias and Eklund have been investigating the role of protein tyrosine phosphatases in cytokine hypersensitivity in myeloproliferative disorders. These studies have lead to a translational project which is discussed further below. The laboratories of Drs. Eleftherios Papoutsakis and William Miller have been using high through put screening to determine the transcriptome of differentiating hematopoietic stem cells. The goal of these studies is to determine the optimum conditions for clinical applications. The recruitment of Dr. Jonathan Licht will enhance several of these programs. Dr. Licht's laboratory focuses of molecular pathogenesis of acute leukemia. Among his contributions include seminal observations regarding the activating mutations in Jak2-protein tyrosine kinase and SHP2-protein tyrosine phosphatase in myeloproliferative disorders and myeloid leukemia.
The Hematological Malignancies Program also has laboratory investigators pursuing the identification of molecular abnormalities involved in lymphoid malignancies. Drs. Steven Rosen and Nancy Krett have a long-standing program in the molecular biology of glucocorticoid resistance in multiple myeloma. Their studies of the molecular mechanisms of resistance have lead to identification of novel therapeutic targets, as discussed below. At the time of the previous program review, Drs. Rosen and Krett continue to be leaders in translating laboratory observations to the clinic. In collaboration with Dr. Singhal, they are extending their analysis of critical signaling pathways in multiple myeloma. Dr. Susan Winandy has been studying dysregulation of Ikaros expression in T-cell lymphoma and leukemia. Her basic sciences studies provide key insights into cell cycle regulation in T-cell leukemia and lymphoma. Dr. Richard Longnecker has a longstanding program investigating the biology of EBV infection and he is a nationally recognized leader in the molecular biology of EBV related cellular transformation. Since the last program review, Dr. Longnecker has formed a collaboration with Dr. Leo Gordon to investigate the impact of latent EBV infection on disease progression or initiation in lymphoma in immuno-compromised patients and within the Eastern Oncology Group. Dr. Winter has led correlative studies in the diffuse large B-cell lymphomas investigating important prognostic indicators such as bcl-6, bcl-2, p53 and p21 expression, identifying subsets that will require specific therapeutic strategies.
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Members of the Hematologic Malignancies Program have been organized into four disease focus groups to facilitate interactions which have increasingly lead to translating results from basic sciences laboratories into clinically related projects. These teams focus on: a.) acute myeloid leukemia and myelodysplasia, b.) multiple myeloma and chronic lymphocytic leukemia, c.) lymphoma, d.) cutaneous T cell lymphoma.
Drs. Platanias and Tallman have made significant progress in extending the observations from Dr. Platanias' laboratory into clinical trials. For example, they have a collaborative project based on Dr. Platania's work on the effect of mTOR inhibition on acute myeloid leukemia cells in vitro. Dr. Platanias has combined this effort with Dr. Tallman's longstanding interest in defining the role of arsenic trioxide for the treatment of AML. In pre-clinical trials, Dr. Platanias found that the mTOR inhibitor rapamycin potentiates the effects of arsenic trioxide on acute myeloid leukemia cells. Based on this promising preclinical data, one phase I/II trial combining arsenic trioxide and the novel mTOR inhibitor Temsirolimus (CCI-771) in relapsed and refractory AML has been designed and the second combining Temsirolimus with high-dose ara-C in patients with first relapsed AML is in development.
Dr. Eklund received a Leukemia and Lymphoma Society of America Translational Research Award to investigate the use of Sodium Stibogluconate in subjects with MDS and secondary AML. These studies are based on the work of Dr. Eklund's laboratory regarding the impact of abnormal SHP2-protein tyrosine phosphatase activity in malignant myeloid disease. In collaboration with Dr. Tallman, Dr. Eklund is performing pre-clinical evaluation of the impact of PTP inhibition with Sodium Stibogluconate on myeloproliferation and cell survival using bone marrow samples from MDS and secondary AML subjects. These studies will be extended to a phase I trial of this agent in these diseases.
Based on studies from his laboratory, Dr. Steve Rosen is investigating the use of the novel Protein Kinase C inhibitor Enzastaurin in the treatment of multiple myeloma and cutaneous T cell lymphoma. Pre-clinical studies in his laboratory demonstrated the utility of this agent for potentiation of the apoptotic effect of dexamethasone in myeloma cells. This is a key observation, because Drs. Krett and Rosen demonstrated that this effect was present even in cell lines with relative glucocorticoid resistance. In additional studies in collaboration with Drs. Kuzel and Guitart, Drs. Rosen and Krett also determined that this agent induces apoptosis in T cell lymphoma lines. Because of this very promising pre-clinical data, clinical trials with an oral form of Enzastaurin are planned for multiple myeloma and cutaneous T cell lymphoma. Drs. Rosen and Krett have also continued their translational studies of 8-chloro and amino adenosine and other novel nucleoside analogues which were praised at the time of the previous program review.
Dr. Richard Longnecker's laboratory has been defining the EBV proteins involved in lymphoma genesis. The basic science work from his laboratory is being applied by Dr. Leo Gordon to investigations of the impact of EBV reactivation on lymphoma in immune compromised patients. The goal of these studies is to develop translational approaches to inhibit the EBV proteins such as LMP2A which are involved in the pathogenesis of malignant transformation in lymphoma. These studies focus both on defining markers of EBV-related lymphoma genesis in at-risk patient populations and developing therapeutic targets.
Dr. Thomas O'Halloran's laboratory has been developing nanotechnologies to improve drug delivery for hematologic malignancies. In collaboration with Drs. Rosen and Winter, these technologies are being extended to develop novel delivery systems for delivery of toxic drugs, such as anthracyclines, to non-Hodgkin's lymphoma. For these studies, Dr. O'Halloran's laboratory is exploring the use of immuno-conjugate nanobins (liposomally encapsulated drugs) for targeted delivery of drug to NHL cells. The goal of these studies is to ultimately develop treatments that will be useful for heavily pre-treated lymphoma patients with extensive previous exposure to such active drugs.
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