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Research

Project 1

Epigenetics of Drug Resistance in Acute Leukemia (AML)  

Jean-Pierre Issa, M.D.
Co-Project Leader, Basic Research

Hagop Kantarjian, M.D.
Co-Project Leader, Clinical Research

Genesis of the Project

DNA methylation and associated epigenetic changes lead to functional alterations in pathways that promote neoplastic development. Therapy targeting DNA methylation and histone deacetylation, another epigenetic modification, has shown activity in myeloid leukemias, and is now part of standard of care in patients with myelodysplastic syndrome (MDS). 

We have identified a DNA hypermethylation signature that characterizes young patients with acute myeloid leukemia (AML) who have a high cure rate following standard cytotoxic chemotherapy. This signature was independent of known prognostic factors and, if validated, would provide an important tool towards personalized therapy in AML. 

Separately and paradoxically, we have shown that progression in AML (diagnosis to relapse) and in MDS ( to AML) is also associated with the progressive acquisition of aberrant DNA methylation that, in this situation, predicts for a poor overall outcome. In proof-of-concept studies, we have shown that treatment with the DNA methylation inhibitor DAC results in tumor-suppressor gene demethylation and reactivation in AML and MDS, associated with a relatively high response rate that correlates with induction of gene expression of the P15 tumor-suppressor. Based on these observations, we hypothesize that DNA methylation profiling identifies a subset of young patients with AML who are curable with standard chemotherapy. 

We further hypothesize that DNA methylation, through separate genes, also contributes to clonal evolution in AML, leading to relapses with drug resistant phenotypes, and that DNA methylation inhibition in remission will delay or eliminate clonal evolution and disease relapse in some patients. Finally, we hypothesize that strategies aimed at enhancing pharmacologic epigenetic reactivation will translate into better therapies for myeloid malignancies. 

To test these hypotheses, we propose the following specific aims

  1. Retrospectively and prospectively validate and extend an epigenetic signature of curability in AML. 
  2. Conduct a randomized clinical trial of remission maintenance in AML using DAC. 
  3. Use a methylated and silenced GFP reporter gene selectable system to identify key pathways and pharmacologic combinations that lead to epigenetic reactivation in neoplastic cells. This project will provide new markers of prognosis in AML and new approaches to therapy that are based on incorporating epigenetic modulation into the standard of care of this disease.

Translational Relevance

This project will extend the progress in our previous funding period to: 1) develop validated tests that can be used for individualized therapy in AML, 2) improve the survival of patients with AML through integrating epigenetic therapy into standard of care, and 3) develop new drug combinations that build on and extend the success of epigenetic therapy in the clinic. 

Specific translational objectives are: 

Aim 1: A validated epigenetic signature that predicts curability would allow personalized medicine by channeling curable patients to standard approaches and non-curable patients to alternate approaches. Identifying the genes responsible for curability in AML would allow the design of strategies to increase the cure rate in this disease. 

Aim 2: Relapse after induction remission accounts for most deaths in AML. Reducing relapses by the clinical approach outlined would increase the cure fraction in this disease. The pharmacodynamic endpoints may identify patients most likely to respond to this approach. 

Aim 3: Modulating epigenetics is now part of the standard of care in some leukemias. Discovering new drug combinations and pathways that lead to enhanced gene reactivation would provide new/improved therapeutics in leukemias. The lessons learned in this project are already being extended to other leukemias (MDS, ALL, CML) and the proof of principle studies as well as the methodology developed/utilized have implications for the management of patients with other malignancies.

Introduction of the Co-Project Leaders

The co-project leaders are Jean-Pierre Issa, M.D., and Hagop Kantarjian, M.D. Dr. Issa is Director at Fels Institute in Philadelphia 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 for Myeloid Leukemia

Jeffrey Molldrem, M.D.
Co-Project Leader, Basic Research

Richard Champlin, M.D.
Co-Project Leader, Clinical Research

Genesis of the Project

There is increasing evidence that lymphocytes can target and inhibit myeloid leukemia cells both in the allogeneic and autologous settings. The potent graft versus leukemia (GVL) effect associated with allogeneic stem cell transplant (SCT) conveys activity against leukemia and contributes to the decreased relapse risk compared with patients who do not receive an allogeneic graft. While GVL can induce long-term remission, the potentially lethal complication of graft-versus-host disease (GVHD) limits overall effectiveness of this treatment approach. We 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 patients with leukemia in the allogeneic setting, and that this effect could be increased by vaccination with appropriate leukemia antigens. We have identified an HLA-A2-restricted monomer peptide, PR1, as a target antigen of CTL that inhibits myeloid leukemia progenitors and kills myeloid leukemia bone marrow cells. We have found that PR1 is processed from both proteinase 3 (PRTN3) and neutrophil elastase (ELA2), which are aberrantly expressed in leukemia. After vaccination with PR1, immune responses were observed in the majority of patients, and persistent remission was documented in some patients with AML, CML, and MDS.  Immune-based therapies with low toxicity could be useful in combined treatment strategies to induce remission in patients with leukemia in the allogeneic setting to enhance GVL and minimize GVHD.  

In this proposal, we will: 

  1. Determine whether phenotype, function, and T cell receptor (TCR) affinity differ between PR1-CTL elicited after vaccination compared to those derived from healthy donors; 
  2. Determine whether aberrant trafficking of PRTN3 and ELA2 can reverse tolerance and facilitate the expansion of central memory PR1-CTL; and 
  3. Determine whether PR1-CTL expressing high affinity TCR can be transferred to patients with AML after T cell-depleted haplo-identical SCT to boost GVL and diminish GVHD.  

Introduction of Co-Project Leaders

The co-project leaders 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 Stem Cell 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

The highly translational components of this proposal are: (1) we will directly study sample material from patients with leukemia who have received many different treatments including the PR1 vaccine that was identified in our laboratory, (2) knowledge gained about affecting PR1 immunity by subcellular antigen processing elements can be immediately tested in patients, and (3) techniques developed in the previous grant period to expand PR1-CTL ex vivo will be tested in SCT recipients.  Therefore, the studies in this proposal depend upon studying patient material to understand mechanisms of immunity versus tolerance. Most importantly, we will directly test our hypotheses in clinical trials in leukemia.

Project 3

P53 Activation as Novel Therapeutic Strategy for Acute Myelogenous Leukemia

Michael Andreeff, M.D., Ph.D.
Co-Project Leader, Basic Research

Marina Konopleva, M.D., Ph.D.
Co-Project Leader, Clinical Research

Jorge Cortes, M.D.
Co-Project Leader, Clinical Research

Genesis of the Project

The main therapeutic challenge in the treatment of myeloid leukemias is the development of strategies that maximize the induction of leukemia cell apoptosis before resistance to chemotherapy develops. p53 is the master switch that determines whether a stressed cell undergoes apoptosis, thus acting as a tumor suppressor. p53 mutations lead to inactivation of this suppressor function. Mouse Double Minute 2 (HDM2) and its homolog HDMX can also inactivate p53 activity: while HDM2 is an ubiquitin ligase that mediates degradation of p53 by ubiquitin-mediated proteolysis, HDMX inhibits the transcriptional activity of p53.  p53 mutations leading to p53 inactivation are rare in newly diagnosed and relapsed AML. There is a reported loss of p53 function through over-expression of HDM2 in approximately 50% of AML cases; expression of HDMX have not been investigated in AML. Restoration of p53 activity by inhibiting HDM2/p53 interaction utilizing non-genotoxic small molecule inhibitors (Nutlin 3a, MI 63) induces apoptosis in AML cells with unmutated p53. While these HDM2 inhibitors dramatically increase p53 levels that initiate transcription of p53 targets, transcription-independent direct interactions of p53 with Bcl-2 family members also occur. Furthermore, chemotherapeutic agents such as cytarabine and daunorubicin synergize with BH3 mimetics, and with MAPK inhibitors, which inhibit induction of anti-apoptotic p21 and regulate the subcellular distribution of p53. Thus, we propose to investigate the molecular and clinical consequences of a clinical trial with small molecule inhibitors of HDM2 (Nutlin 3a, MI-63) and to develop a better understanding of the mechanisms regulating p53 activation and the observed synergism with chemotherapy. If successful, these studies will provide rationale for a novel therapeutic strategy in AML based on the non-genotoxic activation of p53 signaling. Specific Aim 1: Identify the molecular determinants of apoptosis induced by non-genotoxic small molecule inhibitors of HDM2 (Nutlin 3a, MI 63) in leukemia cell lines, primary leukemia cells and stem cells. Specific Aim 2: Determine mechanisms by which HDM2 inhibition synergizes with chemotherapy (Ara-C, Doxorubicin) in AML. Specific Aim 3: Conduct first-in-man Phase I trial of HDM2 inhibitors (Nutlin 3a analog R7112, MI 63) in AML.

Introduction of Co-Project Leaders

The co-project leaders are Michael Andreeff, M.D., Ph.D., Marina Konopleva, M.D., Ph.D., and Jorge Cortes, M.D. 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. 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. Dr. Cortes is one of the worldwide experts in the field of leukemia, with a unique expertise in clinical and translational research in leukemia patients.

Translational Relevance

This project aims at introducing an entirely novel concept into cancer and leukemia therapy: the activation of p53 signaling by pharmacological disruption of the HDM2/p53 protein-protein interaction. We have strong preclinical in vitro and in vivo evidence that disruption of MDM2/p53 induces transcription-dependent and –independent apoptosis in cells with wild-type p53 (utilizing Nutlin 3a from Roche and MI 63 from Ascenta). We found strong synergism with chemotherapy, with Bcl-2 inhibitors such as the BH3-mimetic ABT-737, and with MAPK inhibitors. This proposal aims at better understanding the roles of HDM2 and HDMX, both p53 inhibitors by different mechanisms, of baseline wt p53 levels, and of Arf and NPM1 mutations in this process. These studies will be conducted in vitro in cell lines and in patient samples and in patients with refractory/relapsed AML in a first-in-man clinical trial. The first clinical trial (Aim #3) will determine DLT, MTD and PK of R7112 (a Roche Nutlin 3a analog given orally) and will investigate the impact of the molecular determinants of sensitivity and resistance investigated in Aim #1. Aim #2 will conduct mechanistic studies of HDM2 inhibitor/ chemotherapy combinations and will provide the framework for an anticipated clinical trial in AML. The translational objectives, therefore, are the introduction of MDM2/p53 inhibitors into hypothesis-driven clinical trials.

Project 4

Incorporating FLT3 inhibitors into AML Treatment Regimens

Mark Levis, M.D., Ph.D.
Co-Project Leader, Basic Research

Jorge Cortes, M.D.
Co-Project Leader, Clinical Research

Genesis of the Project

Internal tandem duplication mutations in the FLT3 receptor tyrosine kinase (FLT3/ITD mutations) are one of the most common molecular abnormalities in acute myeloid leukemia (AML) and are associated with significantly worse clinical outcomes.  Several different small molecule FLT3 inhibitors have been studied in AML patients, and most have shown limited but consistent clinical effects.  These inhibitors span a wide range of chemical classes and vary considerably in selectivity for FLT3.  Our previous studies have demonstrated that FLT3 inhibition combined with chemotherapy leads to synergistic cytotoxic effects against FLT3 mutant AML cells, and that FLT3 mutations are present in leukemia stem cells (LSCs).  Preliminary results from ongoing clinical studies of FLT3 inhibitors in relapsed AML patients suggest that chemotherapy followed by successful FLT3 inhibition leads to clinical benefit.  These results are not surprising given the clinical successes of several recently approved tyrosine kinase inhibitors in a variety of cancers, but our findings have raised a number of questions of immediate importance.  To what degree does FLT3 need to be inhibited for maximal benefit?  Will more or less selective FLT3 inhibitors offer the best combination of tolerability and efficacy when given in combination with chemotherapy?  When during the course of AML therapy should the FLT3 inhibitor be administered?  Are FLT3 inhibitors effective against LSCs, and if so, under what conditions?  This proposal aims to address these questions in the context of clinical trials that are either ongoing or are about to begin accruing patients.  The broad goal of this proposal is to better understand how to incorporate FLT3 inhibition into AML therapy so as to improve survival and cure rates for FLT3 mutant AML.

Introduction of Co-Project Leaders

The co-project leaders for this project are Mark Levis, M.D., Ph.D., and  Jorge Cortes, M.D. Dr. Levis, is a well-known physician-scientist who’s expertise include signal transduction biology, molecular pharmacology, and the clinical management of leukemia . His interests are in the use of agents targeting receptor tyrosine kinases for the treatment of acute leukemia, primarily AML.  His laboratory research focuses on how these agents can be successfully incorporated into existing treatment regimens. Dr. Levis has over ten years of experience conducting correlative laboratory studies of clinical trial specimens and directly coordinating clinical trials in AML. Dr. Cortes is one of the worldwide experts in the field of leukemia, with a unique expertise in clinical and translational research in leukemia patients.

Translational Relevance

FLT3 inhibition continues to show great promise for improving the survival of a defined subset of AML patients.  Five years ago, we proposed to study the response of AML patients to FLT3 inhibitors as our project on the leukemia SPORE.  Currently, as a direct result of our “bench to bedside” research, two separate phase III trials of FLT3 inhibitors are underway (Cephalon 204 and MRC AML15).  While these trials may ultimately lead to the approval of CEP-701 for use in AML, their optimal use will still only be crudely defined.  At this point, “bedside to bench” research is needed to optimize the dosing and schedules of these drugs, as well as to better understand why they work and in which patients they should work best.  For the continuation of this project we propose to determine the optimal way of incorporating FLT3 inhibitors into current AML therapy.  Our translational objectives are to establish the degree of FLT3 inhibition necessary for achieving the best clinical responses, and to identify a FLT3 inhibitor that, when combined with chemotherapy, offers the best combination of efficacy and tolerability.  We also wish to determine which FLT3 inhibitors, if any, are effective against leukemia stem cells.  By studying the response of leukemia stem to FLT3 inhibition, alone and in combination with chemotherapy, we can predict whether or not an outright cure can be achieved with this approach, or if, instead, maintenance therapy with a tolerable, potent FLT3 inhibitor is effective at suppressing the re-expansion of the leukemia stem cells.

Core A

Administration

Hagop Kantarjian, M.D.
Jean-Pierre Issa, 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-leaders 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. Both 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

Carlos Bueso-Ramos, 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

Xuelin Huang, Ph.D.
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. The co-leader, Xuelin Huang, Ph.D., and Dr. Berry have served as the principal statisticians in leukemia trials, and have extensive experience in collaborating with the SPORE investigators. Dr. Huang  has designed 50+ clinical trials and reviewed 100+ clinical trial protocols.. He 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.

Programs

Developmental Research Program

William Plunkett, Ph.D.
Co-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

William Plunkett, Ph.D. and Hagop Kantarjian, M.D. are co-directors of this program Dr. Plunkett is a well-known scientist whose research pursuits are related to development of novel therapeutics. Dr. Kantarjian is a distinguished physician-scientist with a strong record of translational research and developmental therapeutics in leukemia.

Developmental Research Program

Career Development Program

Hagop Kantarjian, M.D.
Co-Director

William Plunkett, Ph.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

Hagop M. Kantarjian, M.D. and William Plunkett, Ph.D. serve as co-directors of this program. Dr. Kantarjian is a well-known physician-scientist whose expertise is in leukemia developmental therapeutics. Dr. Plunkett is a distinguished scientist who has extensive experience with career development, training more than 50 scientists and physician scientists as graduate students, postdoctoral fellows and medical oncology fellows.

Career Development Program


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