Research

Project 1

Epigenetics of Drug Resistance in Acute Leukemia (AML)  

Jean-Pierre Issa, M.D.
Co-Principal Investigator, Basic Research

Hagop Kantarjian, M.D.
Co-Principal Investigator, Clinical Research

Guillermo Garcia-Manero, M.D.
Investigator

Genesis of the Project

Subsets of patients with AML can be cured with chemotherapy. However, the majority of patients still die because of resistance to chemotherapy, or relapse subsequent to achieving an initial response. The molecular determinants of this resistance to treatment are unknown. In most patients, there is no evidence of cytogenetic evolution at relapse, and no gene mutations have been identified that can account for treatment resistance in the majority of patients. Epigenetic changes marked by promoter DNA methylation appear to serve as an alternative to mutations in some genes, and such changes have emerged as particularly common in human leukemias.

Based on preliminary data from this and other laboratories, Project 1 proposes the hypothesis that in some cases, treatment resistance in AML is mediated by epigenetic changes involving specific genes. This hypothesis predicts that identification of such epigenetically altered loci and pathways will lead to powerful predictive markers of prognosis in AML, and that modulation of epigenetic information by DNA methylation inhibitors can partially or completely reverse drug resistance. In this project, the investigators will test these hypotheses by identifying genes epigenetically altered in drug-resistant leukemias, testing the prognostic/predictive value of methylation analysis of these genes in AML and conducting in vitro and in vivo studies, including a clinical trial, of the effect of methylation inhibition on AML drug sensitivity.

The group is uniquely positioned to pursue these hypotheses. Their laboratory has described many of the methylation changes in leukemias, and has successfully developed a technique to identify differentially methylated genes. Furthermore, they have already conducted a proof-of-principle clinical trial demonstrating in vivo modulation of epigenetic information by DNA methylation inhibitors, and found clinically promising activity for this approach in AML. Finally, the MD Anderson Leukemia group has a proven track record in conducting clinical trials in AML, along with an established tissue resource that will allow sufficient power to test the predictive/prognostic aims.

Translational Relevance

All aspects of this proposal integrate translational and basic objectives. Broadly, the plan is to identify novel prognostic/predictive markers in acute leukemias and to test the biological hypothesis that drug resistance is epigenetic in some cases in a clinical trial. The project will initially focus on the clinical observation of disease resistance and, using clinical samples, identify candidate genes to explain this phenotype. This laboratory work (gene identification) will then be tested again in clinical samples for validation and identification of prognostic markers. The basic concept that epigenetic changes underlie disease resistance also will be directly tested in patients through a clinical trial of epigenetic modulation to reverse resistance to chemotherapy. Tissue samples from this trial will then be analyzed in the laboratory to verify the hypothesis that DNA methylation inhibitors reactivate the expression of critical genes and to identify potential markers of response to this approach.

Introduction of the Co-Principal Investigators

The co-principal investigators are Jean-Pierre Issa, M.D., and Hagop Kantarjian, M. D. Dr. Issa is chief, Section of Translational Research in the Department of Leukemia, at MD Anderson, and is widely known for his research on DNA methylation and epigenetic changes in malignancies. Dr. Kantarjian is chair, Department of Leukemia, at MD Anderson, and is a recognized leader in clinical research in hematologic malignancies.

Project 2

Adoptive Cellular Therapy of Myeloid Leukemia

Jeffrey Molldrem, M.D.
Co-Principal Investigator, Basic Research

Richard Champlin, M.D.
Co-Principal Investigator, Clinical Research

Genesis of the Project

The potent graft versus leukemia effect (GVL) associated with allogeneic bone marrow transplant (BMT) can produce lasting remissions in patients with myeloid leukemia, but the potentially lethal complication of graft versus host disease (GVHD) limits the effectiveness of this treatment. Donor T cells mediate both GVL and GVHD, although the target antigens recognized by these T cells are not known. The investigators hypothesize that GVL would be enhanced and GVHD reduced or eliminated if the target antigens that drove those responses were identified, and if T cells with GVL antigen specificity could be isolated and adoptively transferred to leukemia patients. They have identified the first human leukemia-associated T cell antigen as PR1, an HLA-A2 restricted nonomer peptide derived from proteinase 3, an aberrantly expressed myeloid-restricted protein in leukemia cells. PR1/HLA-A2 tetramers were used to identify PR1-specific cytotoxic T lymphocytes (CTL) in chronic myeloid leukemia (CML) patients in cytogenetic remission after either interferon or BMT treatment. Using the same deductive strategy that identified PR1, they have shown that CTL with specificity for another antigen, MY4, an HLA-A2 restricted nonomer peptide derived from myeloperoxidase, comprise up to 3% of all CTL in acute myeloid leukemia (AML) patients that are in remission after nonmyeloablative stem cell transplant (NST) but are not detectable in patients that relapse. Furthermore, MY4-specific CTL, like PR1-specific CTL, selectively kill AML cells but not healthy bone marrow cells or epithelial cells, a target of GVHD. In this proposal, the investigators will (1) apply this deductive strategy to uncover additional CTL leukemia-associated antigens (LAA), (2) determine whether LAA-specific CTL are present in patients who receive NST and (3) use LAA peptide/MHC tetramers to select and expand CTL for adoptive transfer into recipients of NST to enhance GVL and reduce GVHD.

Introduction of Co-Principal Investigators

The co-principal investigators are Jeffrey Molldrem, M.D., and Richard Champlin, M.D. Dr. Molldrem has made major contributions in tumor immunology, myeloid leukemia, myelodysplastic syndromes and immunotherapy. Dr. Champlin, chair of the Blood and Marrow Transplantation Department at MD Anderson has made several seminal observations and discoveries in the field of allogeneic SCT. His major goal is to improve the efficacy and reduce the risks of hematopoietic transplantation for treatment of hematopoietic malignancies and selected solid tumors.

Translational Relevance

Currently, the complication of GVHD and the lack of suitable HLA-compatible donors limit the effectiveness of allogeneic bone marrow transplantation. However, if the antigens that drive GVL were known, then targeted immunotherapy strategies could be developed. The work in this proposal will identify relevant leukemia-associated antigens, improve the methods of T-cell expansion and selection then adoptively transfer antigen-specific T-cells to the recipients and follow the developing immune response. This project will validate immunotherapy as a new potential strategy in leukemia and perhaps other cancers. Finally, the laboratory studies following adoptive transfer of the antigen-specific T-cells will allow a close study of the developing immune response against leukemia.

Project 3

Concerted Blockade of Oncoprotein Activity

William Plunkett, M.D.
Co-Principal Investigator, Basic Research

Varsha Gandhi, Ph.D.
Co-Principal Investigator, Translational Research

Jorge E. Cortes, M.D.
Co-Principal Investigator, Clinical Research

Rajyalakshmi Luthra, Ph.D.
Investigator

Genesis of the Project

Some tumors are uniquely dependent for survival upon the activity of oncogenes that confer a gain of function. The example of inhibition of the BCR/ABL function by a variety of means has provided voluminous evidence of the requirement of this oncoprotein for tumorigenesis. Further, the impressive clinical success of imatinib mesylate (STI571, Gleevec) against chronic myelogenous leukemias and acute lymphocytic leukemias expressing this oncoprotein emphasizes the importance of fully developing therapeutic strategies aimed at this target. However, evaluation of therapeutic strategies using imatinib mesylate aimed at the inhibition of oncogene function has demonstrated that failure to completely inhibit the activities of such molecular targets may permit resistance. Indeed, it now appears that several of the mechanisms of resistance to imatinib mesylate are be emerging in the clinic: mutations that decreases inhibitory potency, gene amplification or over-expression that requires greater cellular concentrations of the inhibitor and changes in the pharmacology and disposition of the inhibitor. As such, these defense/resistance mechanisms pose a major problem for the ultimate success of not only the use of imatinib mesylate in CML, but for the general approach of small molecules that are directed at a molecular target. Therefore, additional strategies that complement targeted therapeutics must be developed in anticipation of such events.

The investigators hypothesize those therapeutic approaches that decrease expression of target proteins may complement the actions of specific enzyme inhibitors. Thus, a sequential blockade strategy will target several steps in a single molecular pathway for the production of critical oncoproteins: transcription, translation and the enzymatic activity of oncoproteins. The goals of this project are to develop and validate rationales for the use of multiple agents against a single molecular pathway that generates a protein that is critical for tumorigenesis. In such a sequential blockade of molecular target synthesis and activity, the biological context of tumorigenesis will provide the basis for specificity. In seeking proof of principle evidence for the sequential blockade strategy, they will focus first on the BCR/ABL oncogene that is the etiologic event in chronic myelogenous leukemia. Subsequently, other oncoproteins, such as activated flt3, will be targeted with this strategy.

Introduction of Co-Principal Investigators

The co-principal investigators are all members of the Leukemia Department, who have collaborated with one another as well as other members of this SPORE proposal for many years. Dr. Plunkett is the chief of the Section of Cellular and Molecular Pharmacology; his research has focused on the laboratory development and clinical validation of therapeutic rationales of combination therapies in leukemia. Dr. Gandhi, E. N. Cobb Faculty Scholar, has directed laboratory investigations of new agents and combinations which she has subsequently evaluated in clinical trials with colleagues in the Leukemia Department. Dr. Cortes, Leukemia and Lymphoma Society Scholar and chief, Section of CML, is a physician-investigator whose research interests have been focused on the clinical development of novel agents directed at signaling targets in hematologic malignancies. Dr. Luthra, an investigator on this project, will direct the experimental design and conduct of qualitative analyses of oncogene and control transcripts in investigations involving cell lines and primary leukemia samples.

Translational Relevance

This project could validate the sequential blockade approach to the design of molecularly targeted therapeutics against dominant oncogenes in cancer. In addition to CML, this strategy would have immediate implications for acute leukemias associated with activation of the FLT3 tyrosine kinase, for which kinase inhibitors are currently undergoing clinical evaluations (Project 6).

Project 4

PPAR-gamma Nuclear Transcription Factor: A Novel Target for Leukemia Therapy

Michael Andreeff, M.D., Ph.D.
Co-Principal Investigator

Steven M. Kornblau, M.D.
Co-Principal Investigator

Genesis of the Project

Despite intensification therapy, adult leukemias still have poor prognoses. In AML long-term survival is only 15% to 30%. In ALL, only 30 to 40% of adults are cured. The median survival in MDS is between three and six years; for patients with more advanced disease (RAEB, RAEBT), the median survival is about six to 12 months. Therapy for MDS has not been shown to improve survival, although some patients are cured with chemotherapy or transplantation. The intensive nature of current therapy is often toxic for older patients with poor organ function or other co-morbidities. It is therefore important to identify novel molecular targets, and effective targeting agents capable of eliminating leukemic cells and minimizing toxicity. PPARg (Peroxisome Proliferator-Activated Receptor Gamma) is a nuclear transcription factor, which forms heterodimers with the nuclear retinoid X receptor (RXR). The investigators have demonstrated that PPARg is expressed in the majority of primary human leukemias but not in normal hematopoietic progenitors, and that ligation of PPARg induces differentiation, apoptosis and growth arrest of leukemias. They propose to extend the initial studies on the efficacy and mechanisms of PPARg ligands in acute and chronic lymphoid leukemias, with the goal of developing PPARg ligation as a therapy for hematological malignancies. First, they will investigate the expression of PPARg in leukemias and in leukemic stem cells, and the effects of PPARg ligands on apoptosis and differentiation in primary leukemias. Effects of combined targeting of PPARg and RXR in leukemias will be investigated, with the goal of maximizing transcriptional activation. Second, they will elucidate mechanisms of apoptotic cell death and growth arrest downstream from PPARg ligation. Preliminary data demonstrated that PPARg ligands induced loss of mitochondrial membrane potential and activation of caspases. Finally, they propose to initiate Phase I studies using PPARg ligands in combination with retinoids. These studies will utilize FDA approved PPARƒ× and RXR ligands and the new potent triterpenoid CDDO, a novel PPARƒ× ligand that is developed by them with assistance from CTEP/RAID. The long-term goal of the proposed mechanistic and efficacy studies is to determine the molecular, biological and clinical effects of PPARg/RXR ƒnligation in human leukemia.

Introduction of Co-Principal Investigators

The co-principal investigators are Michael Andreeff, M.D., Ph.D., and Steven Kornblau, M.D. Marina Konopleva, M.D., Ph.D., is an investigator. Dr. Andreeff is a well-known physician-scientist whose expertise is in strategies targeting apoptosis pathways in malignancies, development of cytokine-chemotherapy combinations and multidrug resistance-blocking strategies and the comprehensive analysis of cell signaling, proliferation and apoptosis pathways in leukemia. Dr. Kornblau is a clinical translational scientist who has performed important work evaluating the expression and prognostic importance of cell-cycle and apoptosis-regulating genes in adult hematologic malignancies. Dr. Konopleva is a hematologist/scientist who has made important discoveries in leptin receptor and apoptosis signaling in leukemia, and has developed PPARg as a molecular target in leukemia over the last four years.

Translational Relevance

In addition to establishing the toxicity profile of PPARg/RXR ligand combination and gaining important indications of its activity in patients with leukemia, this project will allow Drs. Andreeff, Kornblau and Konopleva to answer some critical questions on the functional activity of these compounds in inducing apoptosis, differentiation and growth arrest of leukemic cells expressing target receptors, and address potential mechanisms of resistance. These will facilitate the design of future phase 2 studies with these combinations.

Project 5

Molecular Epidemiology of AML

Sara Strom, Ph.D.
Co-Principal Investigator, Translational Research

Elihu H. Estey, M.D.
Co-Principal Investigator, Clinical Research

Genesis of the Project

Little is known about the epidemiological risk factors associated with AML. Even less is known about the role that genetic susceptibility plays in the development and progression of AML. The investigators propose to conduct a multidisciplinary population-based case-control study to investigate genetic susceptibility in patients with AML. Cases will be newly diagnosed AML patients from Harris and the surrounding seven counties accrued from different medical institutions. Controls will be selected through random digit dialing and matched to the cases on age, gender and ethnicity. They will analyze the genotypic, environmental, and sociodemographic contributions to AML risk. This study will provide insight into the role that the susceptibility markers, along with epidemiological, cytogenetic and clinical risk factors, play in the risk of developing AML. These data can also be used to identify patients at increased risk of disease progression and specific therapy-related complications.

Introduction of Co-Principal Investigators

The co-principal investigators are Sara Strom, Ph.D., and Elihu Estey, M.D. Xifeng Wu, M.D., Ph.D., is an investigator, and Dr. Margaret Spitz, M.D., M.P.H., is a collaborator. Dr. Strom is well known for her expertise in conducting large studies integrating molecular and epidemiologic markers. Relevant to this application, she is currently funded to conduct a study of epidemiologic and susceptibility markers associated with the risk of developing MDS. She has also collaborated in clinical epidemiological research with several of the leukemia investigators. Dr. Estey is an outstanding physician-scientist who has made several important discoveries in AML and MDS, and is a prominent authority in these fields. Dr. Wu's main focus is using cutting-edge molecular epidemiologic approaches to study inter-individual differences in susceptibility to carcinogens. Dr. Spitz chairs the Department of Epidemiology, and is widely known for her research on genetically determined susceptibility to tobacco carcinogenesis.

Translational Relevance

Using a molecular epidemiological approach, the investigators will evaluate the role of epidemiologic risk factors and markers of susceptibility in AML risk. This has implications for future larger multi-institutional studies. In addition, it may lead to the identification of individuals or population subgroups at high risk of developing AML. By analyzing risk factor and genotype data among cases, characterized by de novo or treatment-related AML, FAB subsets and specific chromosomal patterns, subgroups of individuals who may have varying susceptibilities to genotoxic exposures as a result of their genetic constitution may be identified. Understanding how genetic predisposition and environmental exposures interact to determine AML susceptibility will allow for the development of prevention strategies in the future.

Project 6

Response of AML Patients to FLT3 Inhibitors

Donald Small, M.D., Ph.D.
Co-Principal Investigator

Jorge Cortes, M.D.
Co-Principal Investigator

Genesis of the Project

AML is the most frequent type of adult leukemia and remains one of the most difficult to cure, with most studies reporting long-term cure rates of 30-40%. Activating somatic mutations of the FLT3 gene in patients with AML have been discovered in the past few years. These mutations are the most frequent genetic aberration in AML and portend a worse prognosis for patients expressing them. Though the mutations occur in different parts of the FLT3 gene, they are all characterized by constitutive activation of the tyrosine kinase domain of FLT3. This presents an excellent molecular target for the development of novel therapeutics that might improve the chance of cure for these patients.

Dr. Small’s laboratory has spent the past several years proving that constitutive activation of FLT3 can transform cell lines and, when expressed in primary cells, results in myeloproliferative disease. They also showed that inhibition of FLT3 resulted in cytotoxicity in modeled cell lines, leukemic cell lines and primary human AML samples. Most recently, his laboratory developed high-throughput cell-based assays that enabled the screening of thousands of small molecules for their ability to inhibit FLT3 in a highly potent and selective manner. This has now led to a clinical trial of FLT3 inhibitors in AML patients with FLT3 activating mutations at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins that will also be activated at MD Anderson. This allows important correlative studies to be performed on the cells from these patients, which will enable the investigators to optimize the use of this new class of drugs in patients with AML, improving the prognosis and decreasing the toxicity of current AML therapy.

Introduction of Co-Principal Investigators

The co-principal investigators for this project are Donald Small, M.D., Ph.D., and Jorge Cortes, M.D. Dr. Small is an acknowledged leader in the area of FLT3 studies in AML. His efforts in the laboratory have culminated in the current human trials of FLT3 inhibitors in AML. He was the first to clone the human FLT3 gene almost 10 years ago, and he has continued to investigate its role in leukemic transformation. His laboratory was the first to show that small molecules could inhibit FLT3 tyrosine kinase activity, thus interfering with signaling. This induced cytotoxicity in modeled cells, leukemic cell lines and primary human AML samples expressing constitutively activating forms of FLT3 mutations. They also developed the high-throughput cell-based screening assay for FLT3 inhibitors that lead to the discovery of CEP-701 as a very potent, highly selective inhibitor of FLT3. He also serves as the co-PI of the CEP-701 trial at Johns Hopkins. Dr. Cortes is an established leader in clinical leukemia trials who will be leading the FLT3 inhibitor trial at MD Anderson. Dr. Levis, investigator, is a highly promising young physician-scientist who has spent the past two years working in Dr. Small’s laboratory and who will join the JHU Oncology faculty in June of this year.

Translational Relevance

This program has important implications for optimizing molecular targeted therapy against FLT3 to improve the prognosis and minimize the side effects of chemotherapy in AML. It will lead to a better understanding of why patients respond and why they may be resistant, thus leading to the identification of additional molecular pathways to target in future studies.

Project 7

Developmental Research Project - Summary for Director’s Overview
W. Arap, M.D., Ph.D. Feb 2005

Wadih Arap, M.D., Ph.D.
Co-Principal Investigator

Renata Pasqualini, Ph.D.
Co-Principal Investigator

Targeted drug delivery offers a platform for the development of safer and more efficient therapies in leukemia. We reasoned that profiling of leukemia cells with small protein fragments from a large collection of peptides displayed on the surface of small, virus-like particles (phage) would allow for the identification of novel therapeutic targets. Phage collections can be incubated with the leukemia cells and particles that bind to receptors on the surface of leukemia cells can be recovered. Some of these receptors may turn out to be important in the progression of the disease. Our specific objectives are to isolate peptides that preferentially bind to leukemia cell surface markers, identify the corresponding receptors, and evaluate the lead ligand - receptor pairs for targeted therapy in leukemia. Using phage display technology termed Biopanning and Rapid Analysis of Selective Interactive Ligands, we profiled nine human leukemia cell lines. Our screening yielded three clones with cyclic insert sequences that exhibited strong binding to leukemia cell lines and to bone marrow from eight AML and seven ALL patients. By conducting matching searches in protein databases, we found that some of these peptide motifs share homologous sequences with proteins that have known bio-functional relevance to leukemia. Subsequently, we dentified neuropilin-1 (NRP-1) as the receptor recognized by one of these peptides. Since NRP-1 plays an important role in immune regulation as well as in tumor growth and spread, we tested if the peptide has any bio-functional effect in targeting the receptor in vitro and whether it could deliver a pro-apoptotic moiety into leukemia cells. Results from cell proliferation and viability assays indicate that the peptide, in conjugated from, resulted in significant cytotoxicity in all nine leukemia cell lines. Work is underway to validate the therapeutic efficacy of this peptide in leukemia mouse models. Additionally, we intend to evaluate and characterize other promising candidates that were generated from our search. Our findings can be clinically meaningful in that successfully validated peptides can be used as tags to guide targeted therapy of leukemia. One or more of these peptides can potentially serve as a drug lead and may provide a novel therapeutic option in leukemia. We strongly believe that our objective will be met as our research efforts continue to be supported in part through the Leukemia SPORE and more importantly via integrating the complementary expertise of other SPORE members.

Core A

Administration

Hagop Kantarjian, M.D.
Jean-Pierre Issa, M.D.
Elihu Estey, M.D.
Co-Leaders

Genesis of the Core

We believe that the projects described above represent innovative, well designed, hypothesis-driven and highly feasible multidisciplinary translational research. To accomplish this research, we must have scrupulous administration, open communication and meticulous fiscal oversight. These are the goals of Core A.

Introduction of the Co-Leaders

The co-leaders of Core A are the two co-principal investigators for the Leukemia SPORE, Hagop M. Kantarjian, M.D., and Jean-Pierre Issa, M.D. Dr. Kantarjian is a well-known physician-scientist whose expertise is in developmental therapeutics in leukemia. Dr. Issa is an eminent researcher who has made major contributions to the area of mechanisms of methylation in cancer. The third co-leader, Dr. Elihu H. Estey, is a distinguished physician-scientist with a strong background in clinical research, translational research, biostatistics and data management and analysis. All three co-leaders have extensive experience in the successful conduct of large-scale translational research studies in leukemia.

Core B

Pathology and Tissue Core

Steven Kornblau, M.D.
Leader

Jean-Pierre Issa, M.D.
Co-Leader

Effective tissue procurement and utilization is vital for meaningful translational research activities. The Pathology and Tissue Core will work with each SPORE project and the Biostatistics and Data Management Core to ensure efficient and highly coordinated procurement, use and storage of blood and bone marrow samples. The Core will obtain and maintain a repository of blood samples (including peripheral blood, bone marrow biopsies and bone marrow aspirates) for laboratory use, with an effective coding system for all laboratory specimens to ensure patient confidentiality and prevent experimental bias. Continuous communication between the investigators, research nurses, biostatisticians and hematopathologists, as well as standardized operating procedures for activities will provide for optimal tissue collection and accurate processing, analysis and storage of each sample. Thus, the functions of the Pathology and Tissue Core are to facilitate acquisition, preservation, analysis and dispersal of clinical samples and to provide hematopathologic characterization and specimens for all project investigators.

The Tissue Procurement and Hematopathology Core has the following objectives:

• Develop and maintain a repository of blood and bone marrow specimens, including intact cells, serum, cellular DNA, RNA and protein, from patients with leukemia and MDS (including patients who are newly diagnosed, in remission or in relapse) receiving care or evaluation at MD Anderson Cancer Center
• Distribute tissue specimens to SPORE investigators for analysis and provide expertise in the interpretation of studies performed on tissue sections within SPORE projects
• Provide comprehensive histologic characterization of blood and marrow samples used in SPORE projects, including specimens from patients entered onto clinical protocols
• Maintain a comprehensive, prospective interactive database with detailed clinical and pathologic data for patients with leukemia and MDS receiving care or evaluation at MD Anderson Cancer Center
• Facilitate inter-SPORE collaborations through sharing of blood and marrow resources.

Core C

Biostatistics and Data Management

Donald Berry, Ph.D.
Leader

Terry L. Smith, M.S.
Co-Leader

Genesis of the Core

Expert assistance with biostatistical and data management issues is essential to the design and conduct of translational research studies. This support involves issues of study design, including appropriate sample size for primary objectives, power for detecting alternative hypotheses, identifying unmet needs, developing new methodology for biomarker-integrated translational studies and monitoring the conduct and possible early termination of such studies. Once data are collected, they must be efficiently entered, managed and stored with the highest integrity and attention to data quality, safety and confidentiality. These are the goals of the Biostatistics and Data Management Core.

Introduction of the Core Co-Leaders

Donald Berry, Ph.D., is a renowned expert in the field of statistical design and analysis of translational cancer trials, and the chairman of the Department of Biostatistics. The co-leader, Terry L. Smith, and Dr. Berry have served as the principal statisticians in leukemia trials, and have extensive experience in collaborating with the SPORE investigators. Terry Smith has collaborated with the Leukemia Department on over 50% of all their studies in the past 25 years. She is extremely knowledgeable about leukemia, previous studies, existing databases and needs, and is best positioned to assist Dr. Berry and the Leukemia SPORE in the biostatistical needs. John Cook will provide expertise regarding the establishment of the Leukemia SPORE database, its communication with other existing databases (AML P01 database, Blood and Marrow Stem Cell Transplant database) and the conversion of the current Leukemia Department database to a more flexible system that provides multiple levels of security and allows interaction and merging of data from the other databases.

Programs

Development Research Program

Jean-Pierre Issa, M.D.
Director

Hagop Kantarjian, M.D.
Co-Director

Genesis of the Program

To assure that the Leukemia SPORE retains its translational relevance and impact, the SPORE leadership must be ready to re-engineer or discard projects that fail to live up to their original potential. Replacement projects will be developed through the Leukemia SPORE Developmental Research Program. The primary goal of this program is to perform new and innovative small-scale research studies in order to develop new projects that can be used to replace any non-performing SPORE projects. Through the Developmental Research Program, researchers will be encouraged to test new approaches and take intellectual risks relevant to leukemia research.

Introduction of the Directors

The director of this program is Jean-Pierre Issa, M.D. The co-director is Hagop M. Kantarjian, M.D. Dr. Issa is an eminent researcher who has made major contributions to the area of leukemia methylation and its significance in cancer. Dr. Kantarjian is a distinguished physician-scientist with a strong record of translational research and developmental therapeutics in leukemia.

Development Research Program

Career Development Program

Hagop Kantarjian, M.D.
Director

Jean-Pierre Issa, M.D.
Co-Director

Genesis of the Program

Training and mentoring of young investigators, and the support of their research efforts, is a primary mission of the Leukemia SPORE. Dr. Kantarjian and his senior investigators have a long history of mentorship. Through the SPORE Career Development Program, senior medical or laboratory-based postdoctoral fellows and junior faculty who wish to develop careers in translational leukemia research will be recruited. Exceptional, established senior faculty who wish to redirect or extend their ongoing research programs to include leukemia translational cancer research will be eligible for this program.

Introduction of the Directors

The director of this program is Hagop M. Kantarjian, M.D. Jean-Pierre Issa, M.D., will serve as co-director. Dr. Kantarjian is a well-known physician-scientist whose expertise is in leukemia developmental therapeutics. Dr. Issa is a distinguished physician-scientist with a strong record of translational research in methylation and leukemia.

Career Development Program