Research

Click the red plus signs to see detailed information on research projects within The Joe Moakley Leukemia SPORE.

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

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

Genesis of the Project

Epigenetic therapy aims to reprogram gene expression in cancer cells to achieve a therapeutic effect. To date, DNMT inhibition is the most effective form of epigenetic therapy in myeloid leukemias. Through SPORE funding, project investigators developed (and validated) a live cell assay to screen for drugs that achieve the same degree of epigenetic reprogramming as DNMTi. Using this screen, they discovered a new class of epigenetic drugs that activate silenced expression through inhibition of CDK9. CDK9 is a transcriptional regulator previously linked to gene activation through the pTEFb complex that phosphorylates RNAPII and promotes elongation. The new data place CDK9 at the heart of a node that regulates both gene silencing and activation. As such, targeting CDK9 has pleotropic effects on gene expression that appear ideal from an anti-tumor perspective: One observes simultaneous gene activation (of tumor suppressors), repression (of oncogenes), and induction of an interferon response which may be immune-sensitizing.

Known CDK9 inhibitors (flavopiridol, SNS-032) have activity in leukemias but are marred by serious chemotherapy like toxicities. Examining published PK/PD data, the investigators found that doses in use clinically were at least an order of magnitude higher than what is needed to inhibit CDK9, and speculate that the toxicity observed is typical of cross-target inhibition of CDK1/2. Thus, much lower doses of CDK9 inhibitors may preserve activity (through epigenetic effects of CDK9 inhibition) while reducing toxicity (by avoiding other CDKs). This is similar to the development of decitabine where switching from cytotoxic doses (abandoned in the 1980s because of severe delayed and unpredictable myelosuppression) to low “epigenetic” doses (100 mg/m²/ course versus 1,000-2,0000 mg/m²/course) uncovered its remarkable activity in AML and MDS. By analogy, project investigators hypothesize that low doses of CDK9 selective drugs may preserve activity (through epigenetic effects of CDK9 inhibition) while reducing toxicity (by avoiding other CDKs). In this SPORE renewal, project investigators will elucidate the mechanism of epigenetic effects of CDK9, determine the downstream effects of CDK9 inhibition on cellular function and immune responses, and conduct a clinical trial of a newly developed CDK9 selective drug in myeloid leukemias.

Specific Aim 1. Elucidate the mechanisms of CDK9 mediated epigenetic silencing effects

Translational goal. Clarify the contribution of CDK9 inhibition to the potential of improving epigenetic therapy; this can be readily exploited as a novel therapy in clinical trials in leukemia and MDS

Specific Aim 2. Study the functional consequences of CDK9 inhibition alone and in combination with DNMT3A inhibition

Translational goal. Develop rational strategies and new combinations involving CDK9 inhibition, in preparation for clinical trials of a novel, CDK9 selective drug.

Specific Aim 3. Pre-clinical and early clinical studies of MC180295, a new selective CDK9 inhibitor.

Translational goal. Perform IND enabling studies to introduce a new CDK9 selective drug into clinical trials, and bring this drug to a first-in-human trial using dual endpoints of MTD and biologically optimal dose, as done for hypomethylating drugs.

Translational Relevance

The project focuses on improving epigenetic therapy. In the previous SPORE funding periods, project investigators pioneered and championed epigenetics and epigenetic therapies in cancer research. They redeveloped decitabine preclinically and clinically as epigenetic therapy at 1/20th of the doses established in the 1980s. They translated their laboratory research into phase I, II and FDA pivotal trials, resulting in the FDA approval of decitabine for the treatment of MDS in 2006, and the EMEA approval for the treatment of elderly AML in Europe in 2012. They also explored the 5-day versus 10-day schedules, now pursued by other investigators. Epigenetic therapy with decitabine and azacitidine improved survival in MDS and AML, but only modestly. The median survival in MDS with epigenetic therapy improved to 2.5 years. Patients with MDS failing hypomethylation therapy have a very poor prognosis, with a median survival of 4-6 months. In AML, single agent hypomethylating drugs produce median survivals of only 7-8 months. These findings highlight the shortcomings of current epigenetic therapy in leukemia and MDS, and stress the need to improve it, in order to further prolong survival of more than 40-60,000 patients with AML or MDS diagnosed annually. Epigenetic therapy, pioneered in myeloid leukemias, is now under evaluation in the settings of post allogeneic stem cell transplantation, in lymphomas, and in solid tumors in combinations that include immunotherapy (checkpoint inhibitors), with promising results reported in lung and ovarian cancer. Thus, advances in epigenetic therapy realized through the SPORE project may benefit knowledge in, and therapy of other cancers.

In the immediate previous SPORE funding period, project investigators have: 1) developed reporter cellular assays for reactivation of epigenetically silenced gene expression; 2) screened an FDA approved drug library and identified multiple drugs with unsuspected epigenetic activity; 3) discovered that cardiac glycosides can reactivate silenced gene expression through calcium signaling; 4) elucidated a new mechanism of gene silencing that involves calcium fluxes signaling to CAmKII, triggering nuclear to cytoplasmic shifts in epigenetic regulators such as MeCP2; 5) conducted a clinical trial of one of the newly discovered epigenetic drugs (arsenic trioxide, ATO) showing superior responses and survival for decitabine + ATO compared with decitabine alone in MDS; 6) studied combinations of decitabine with various histone modifiers, showing specificity for histone methylase inhibitors but lack of specificity for HDAC inhibitors; 7) conducted a new drug screen of a natural compound library and identified several leads for epigenetic drug development; and 8) identified CDK9 as a new regulator of epigenetic silencing and target of one of the new drugs discovered. In addition, because of the SPORE efforts, they leveraged vertical collaborations with the drug industry to develop new oral formulations of decitabine (Astex) and azacitidine (Celgene), and to develop a new-generation more potent epigenetic agent, guadecitabine (Astex).

In the current SPORE project, the investigators will focus on novel approaches to enhance epigenetic therapy through modulation of CDK9, involved in epigenetic silencing in proliferating cells. The investigators propose that targeting CDK9 at minimal concentrations can activate tumor-suppressor genes, trigger an immune gene signature, and repress super-enhancer linked oncogenes in AML, while avoiding serious side effects observed in previous experiences with less selective CDK inhibitors. Following extensive screening, they identified a novel selective CDK9 inhibitor. They will study the mechanisms of epigenetic regulation by CDK9, perform pre-clinical studies of the novel CDK9 inhibitor alone and in combination with decitabine, perform IND-enabling studies for the new drug and conduct a phase 1 study with dual pharmacodynamic and toxicity endpoints. Throughout, they will assess samples on therapy for molecular signatures that may define responsiveness/resistance to this form of therapy.

If successful, this project could introduce a new form of epigenetic therapy for leukemia and other cancers.

Introduction of the Co-Project Leaders

The co-project leaders are Marina Konopleva, M.D., Ph.D., and Jean-Pierre Issa, M.D. Konopleva is a Professor and active member of the clinical faculty in the Departments of Leukemia and Stem Cell Transplantation. She is a recognized leader in clinical translational investigations and has developed clinical trials based on laboratory discoveries. Issa is President & Chief Executive Officer of Coriell Institute for Medical Research and is an expert in the study of epigenetics – how the turning on and off of genes affects our health – and to better understanding epigenetic changes in aging and cancerous cells. 

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

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

Genesis of the Project

The long-term goal of this project is to develop immune therapies that target aberrantly expressed proteases in blasts and leukemia stem cells. The investigators identified a T cell receptor (TCR)-like antibody (8F4) with specificity for a conformational epitope of PR1 (VLQELNVTV), a peptide derived from leukemia-associated protease antigens (LAAs) P3 and NE, that are bound to HLA-A2. 8F4 induces complement-dependent cytolysis (CDC) of AML and leukemia stem cells (LSC) and inhibits AML progenitor cell growth but not normal bone marrow progenitors, which supports further study of 8F4 as a potential therapeutic monoclonal antibody for AML. The preliminary data generated by project investigators showed that 8F4 prevented AML engraftment in vivo, and that humanized 8F4 eliminated established human AML in a xenogeneic animal model. Thus, 8F4 is the first TCR-like monoclonal antibody that inhibits growth of AML and LSC and eliminates AML in vivo. In the previous Leukemia SPORE period, project investigators have characterized the activity of 8F4 against human AML, performed pre-clinical treatment validation studies of 8F4, and secured cGMP material of 8F4 monoclonal antibody for phase I clinical trials, in collaboration with the drug industry (Astellas). Thus, the work in this project supports the overall goal of the SPORE grant to discover, develop and clinically test novel therapies for leukemia.

While studies of 8F4 appear promising, a significant reduction of LSC required prolonged treatment with 8F4 in PDX-bearing mice. Antibodies for the treatment of cancer, including leukemia, have limited effectiveness as single agents. Also, additional studies in PDX models showed that 8F4 treatment of some primary AML resulted in the growth of a population of blasts with low PR1 expression but without changes in overall HLA-A2 expression. This potential mechanism of 8F4 resistance or escape suggests that increasing the potency of 8F4-based therapy will be important for its successful clinical application. In the current proposal, the investigators seek to characterize the mechanism of PR1 down-regulation on AML after 8F4 treatment, and to explore alternative approaches to increase the potency of 8F4, based on established treatment strategies that have demonstrated significant clinical activity as single agents in patients with CD19+ leukemia, (e.g. treatment with CD19xCD3 bispecific antibody blinatumomab; CD19 CAR T cells). The hypothesis is that AML will be more effectively eliminated by redirecting polyclonal T cells to target PR1/HLA-A2 through modifying T cells with an 8F4-CAR or with treatment using an 8F4xCD3 bispecific antibody. To test this hypothesis, they propose the following Specific Aims:

Aim 1. Conduct a first-in-human Phase I clinical trial of 8F4 in HLA-A2⁺ refractory/relapsed AML

Translational goal. Evaluate the safety and potential efficacy of h8F4 therapy in AML. If successful, expand this investigation into phase II-III pivotal clinical trial as indicated by the efficacy-toxicity and translational results on serial samples evaluating response-resistance mechanisms.

Aim 2. Characterize AML blasts and leukemic stem cells in patients treated with 8F4.

Translational goal. Evaluate mechanisms of resistance on 8F4 therapy to decide whether such mechanisms can be potentially circumvented with new forms of 8F4 targeted therapies (bispecific monoclonal antibody constructs; CART cellular therapy targeting 8F4).

Aim 3. Characterize mechanisms of PR1 cross-presentation, and characterize alternative treatment approaches to address resistance to 8F4 treatment.

SubAim 3A. Characterize mechanism of PR1 down-regulation after 8F4 treatment.

SubAim 3B. Study the preclinical activity of 8F4-CAR T cells on AML.

SubAim 3C. Conduct pre-clinical validation and safety studies of 8F4-CAR T cells in animal models.

Introduction of Co-Project Leaders

The co-project leaders are Jeffrey Molldrem, M.D., and Richard Champlin, M.D. Molldrem has made major contributions in tumor immunology, myeloid leukemia, myelodysplastic syndromes and immunotherapy. 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 project explores the benefits of immunotherapies in leukemia. Harnessing the immune system to treat cancer is producing dramatic results in cancer. Examples include various monoclonal antibodies targeting CD19, CD22, CD33 and CD123, among many others; bi-specific monoclonal antibody constructs targeting many of the same surface signals, chimeric antigen receptor (CAR) T-cellular therapy targeting CD19 and CD22, and checkpoint inhibitors in a wide variety of solid and hematologic cancers. Project investigators have a long-standing research commitment and involvement in developing immunotherapy for myeloid leukemias, initially with the PR1 vaccine (now transferred as a vertical collaboration with a startup company, The Vaccine Company) and, more recently, with the development of the human 8F4 monoclonal antibody. The potential therapeutic success of this monoclonal antibody, developed through SPORE-funded research will have broad applications across leukemias and other hematologic malignancies, both in the setting of active disease and for elimination of minimal residual disease. In the immediate previous SPORE funding period, project investigators accomplished the project aims to characterize the specificity and mechanisms of action of 8F4, and large scale production of cGMP quality drug, translating it into a clinical trial in AML.

In the current funding period, project investigators will continue their focus on immune therapy with 8F4, a first-in-class TCR-like mAb directed at the leukemia-associated PR1/HLA-A2 complex. To support clinical testing of 8F4, the MD Anderson signed an agreement with Astellas Pharma to support large-scale production of sufficient cGMP material to complete up to phase IB clinical testing. There is now sufficient drug production to test the safety of the 8F4 monoclonal antibody in a first-in-human phase I clinical trial for patients with refractory-relapsed AML, in the second half of 2017. Thus, the work in this project supports the overall goal of the Leukemia SPORE to discover, develop and clinically test novel therapies for leukemia.

While the results with 8F4 appear promising, a significant reduction of leukemia stem cells (LSC) required prolonged treatment with 8F4 in mice engrafted with patient-derived xenografts (PDX). Moreover, antibodies for the treatment of cancer, including leukemia, have limited effectiveness as single agents. Additional studies in PDX models have shown that 8F4 treatment of some primary AML PDX resulted in the outgrowth of a population of blasts with low PR1 expression but without changes in overall HLA-A2 expression. Increasing the dose of 8F4 eliminated subsets of AML with high and low PR1 expression. However, the potential for 8F4 resistance or escape suggests that increasing the potency of 8F4-based therapy will be important for the successful clinical application of this approach. In the current proposal, the project will characterize the mechanism of PR1 down-regulation in AML after 8F4 treatment, and explore alternative approaches to increase the potency of 8F4, based on recently established treatment strategies with bispecific antibodies and CARs that have demonstrated significant clinical activity as single agents in patients with CD19+ leukemia, such as treatment with CD19xCD3 bispecific antibody (blinatumomab) and CD19 CAR T cells. The investigators hypothesize that AML will be more effectively eliminated by redirecting polyclonal T cells to target PR1/HLA-A2, by modifying T cells with an 8F4-CAR, or with treatment using an 8F4xCD3 bispecific antibody. The new Specific Aims are to: 1) Conduct a first-in-human phase I clinical trial of 8F4 in HLA-A2⁺ in refractory/relapsed AML. 2) Characterize AML blasts and LSC in AML patients treated with 8F4 monoclonal antibody. 3) Characterize the mechanisms of PR1 cross-presentation, and characterize alternative treatment approaches to address resistance to 8F4 treatment, including developing and evaluating the activity of 8F4-CAR T cells in AML animal models.

If successful, this project will result in a completely novel immunotherapeutic strategy in the form of 8F4 monoclonal antibody or cellular therapies that may benefit cancers expressing this target. This is not only applicable to AML, but also to other cancers, e.g. breast and lung cancer, which cross-present the PR1 target antigen and are susceptible to 8F4 killing.

Katy Rezvani, M.D., Ph.D.
Co-Project Leader, Basic Research

 Elizabeth Shpall, M.D.
Co-Project Leader, Clinical Research

Genesis of the Project

Adoptive cell therapy has emerged as a powerful treatment modality for advanced cancers refractory to conventional therapy. Remarkable responses have been achieved in patients receiving autologous CD19-redirected T cells for the treatment of acute lymphoblastic leukemia (ALL) and other B lymphoid malignancies. CAR-modified T-cells have limitations: 1) The generation of autologous products for individual patients is logistically cumbersome and restrictive for widespread clinical use 2) The manufacturing of CAR T-cells often takes several weeks, making it impractical for patients with rapidly advancing disease. 3) It is not always possible to generate clinically relevant doses of CAR T-cells from heavily pre-treated patients.

A previously collected allogeneic product could overcome these limitations; but allogeneic T-cells (even if HLA-matched) carry the risk of graft-versus-host disease (GVHD), mediated through native αβ T-cell receptor. Natural killer (NK) cells provide an attractive alternative to T cells for CAR engineering. Functional NK cells can be derived from several sources. Autologous NK cells can be reproducibly generated in vitro, but have limited activity against autologous tumors, which is unlikely to be overcome by CAR engineering. Cord blood (CB) is a readily available source of allogeneic NK cells with clear advantages. CB is available as an off-the-shelf frozen product, an advantage bolstered by methods to generate large numbers of highly functional NK cells from frozen CB units ex vivo. This holds promise for widespread scalability that cannot be replicated with individual adult donors who require screening and leukapheresis. One disadvantage of NK cells is their lack of persistence after adoptive transfer in the absence of cytokine support. Although CAR-engineered NK cells may improve their persistence, they may also exert potentially serious toxicity, such as cytokine release syndrome (CRS) or off-tumor/on-target toxicity, as reported with CAR T-cells.

The long-term objective of project research is to develop novel cell-based therapies using CB-derived NK cells, and to enhance their effector function against ALL by genetically engineering them to redefine their specificity and enhance their potency and safety. Project investigators have developed a novel strategy to redirect the specificity of CB-derived NK cells to target CD19+ malignancies by genetically modifying them with a retroviral vector (iC9-2A-CD19.CAR-CD3zeta-2A-IL-15) that; 1) incorporates the gene for CAR.19 to redirect their specificity; 2) ectopically produces IL-15, to support their survival and proliferation; and 3) expresses a suicide gene, inducible caspase-9 (iC9), that can be pharmacologically activated to eliminate transduced cells. Using this approach, they showed that engineered CB-derived NK cells exhibited striking efficacy, and proliferated and persisted in vivo. They can also be efficiently eliminated to limit toxicity. These pre-clinical data provide the rationale to take this approach to the clinic.

Based on these data, the investigators hypothesize that the antileukemic activity of NK cells against ALL can be enhanced by engineering them to express a CAR against CD19 and by protecting them from the immunosuppressive cytokine TGF-beta. To test the hypothesis, they propose the following Specific Aims:

Specific Aim 1. Test the safety and anti-leukemic efficacy of CB-NK cells engineered to express CAR.CD19 to redirect their specificity, IL-15 to enhance their in vivo persistence and a suicide gene based on iC9 as a safety measure.

Translational goal. Obtain clinical toxicity and efficacy results to guide further development and expansion of this novel NK-CAR cellular therapy.

Specific Aim 2. Trace the fate of genetically modified CB-derived NK cells after adoptive transfer and study their expansion and reconstitution in vivo.

Translational goal. Validate the long-term viability, efficacy and safety of the transferred NK-CAR cells.

Specific Aim 3. Determine if a novel CAR construct based on iC9-2A-CAR19-zeta-2A-IL15 that also includes the dominant-negative TGF-β type II can protect NK cells from the TGF-β rich immunosuppressive tumor microenvironment.

Translational goal. Establish if targeting the TGF-β/SMAD signaling axis using a novel retroviral construct that, in addition to CAR.CD19 and IL-15, includes the gene for the dominant-negative version of human TGFβ receptor II (TGFβ-DNRII), can protect the transduced NK cells from the immunosuppressive tumor microenvironment for next-generation clinical studies.

Introduction of Co-Project Leaders

The co-project leaders for this project are Katy Rezvani, M.D., Ph.D. and Elizabeth Shpall, M.D. Rezvani is Professor of Medicine, Director of Translational Research, Medical Director of the MD Anderson GMP and Cell Therapy Laboratory and Chief, Section of Cellular Therapy, Department of Stem Cell Transplant and Cellular Therapy, MD Anderson She has an active research laboratory program in transplantation immunology where the focus of her research group is to study the role of natural killer cells (NK) cells in mediating immunity against leukemia, and to understand the mechanisms of tumor-induced NK cell dysfunction. Shpall is the Director of the Cell Therapy Laboratory and the Cord Blood Bank and Deputy Chair of the Department of Stem Cell Transplantation and Cellular Therapy. She has more than 30 years of experience performing stem cell transplants and translating stem cell graft manipulations from the laboratory to the clinic.

Translational Relevance

This project explores a novel form of cellular immunotherapy, using off-the-shelf engineered cord blood-derived natural killer cells for the treatment ALL. Adoptive cell therapy has emerged as a powerful treatment modality for advanced cancers refractory to conventional therapy. Most notable are the remarkable responses seen in patients receiving autologous CD19-redirected T cells for the treatment of ALL and other B lymphoid malignancies. Nonetheless, CAR-modified T-cells have a number of limitations: Generation of autologous products is logistically cumbersome and restrictive for widespread use; manufacturing of CAR T-cells takes several weeks; it is not always possible to generate clinically relevant doses of CAR T-cells from heavily pre-treated patients. A previously collected allogeneic product could overcome these limitations, but allogeneic T-cells (even HLA-matched) carry a risk of graft-versus-host disease (GVHD), mediated through their native αβ T-cell receptor. Natural killer (NK) cells provide an attractive alternative to T-cells for CAR engineering. Functional NK cells can be derived from several sources. Autologous NK cells have reduced activity against autologous tumors. Cord blood (CB) is a readily available source of allogeneic NK cells with clear advantages. CB is available as an off-the-shelf frozen product, an advantage that has been bolstered by methods to generate large numbers of highly functional NK cells from frozen CB units ex vivo. Thus, the generation of CAR-transduced NK cells from frozen CB units stored in large global CB bank inventories holds promise for widespread scalability that cannot be replicated with individual adult donors who require screening and leukapheresis. A major disadvantage of NK cells is their lack of persistence after adoptive transfer in the absence of cytokine support. CAR-engineered NK cells may also exert potentially serious toxicity, such as cytokine release syndrome (CRS) or off-tumor/on-target toxicity, as reported with CAR T-cells.

The long-term objective of the research in the project is to develop novel cell based therapies using CB-derived NK cells, and to further enhance their effector function against ALL by genetically engineering them to redefine their specificity and enhance their potency and safety. The specific aims are: 1) Conduct a first-in-human clinical trial to test the safety and anti-leukemic efficacy of CB-NK cells that have been engineered to express CAR-CD19 to redirect their specificity, IL-15 to enhance their in vivo persistence and a suicide gene based on iC9 as a safety measure. The study is approved by the IRB and the FDA (protocol 2016-0641, IND 17321). 2) Trace the fate of genetically modified CB-derived NK cells after adoptive transfer and study their expansion and reconstitution in vivo; and correlate with disease response. 3) Determine if a novel CAR construct based on iC9-2A-CAR19-zeta-2A-IL15 that also includes the dominant-negative TGF-β type II receptor can protect NK cells from the TGF-β rich immunosuppressive tumor microenvironment.

If successful, the project could produce a novel form of NK-CAR cellular therapy that would be readily available (off-the-shelf), and potentially more effective and less toxic than the current CAR-T cellular therapies. The strategy could later expand to other cancer targets, including CD22, CD33 and CD123.

Giulio Draetta, M.D., Ph.D.
Co-Project Leader, Basic Research

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

Genesis of the Project

Metabolic reprogramming of the key energy-generating pathways is one of the key oncogenic properties of cancer, including leukemia. While accelerated glycolysis is considered to be most common feature of tumors, the SPORE project investigators and others have shown that AML cells are unique in their mitochondrial characteristics and have an increased reliance on oxidative phosphorylation (OxPhos). Unlike normal cells, AML cells, including leukemia-initiating cells, overexpress anti-apoptotic BCL-2 protein and are unable to upregulate glycolysis sufficiently after OxPhos is inhibited due to a low spare reserve capacity. This unique metabolic and mitochondrial biology makes AML vulnerable to strategies that target OxPhos and BCL-2. Inhibition of cellular respiration with IACS-010759, a novel inhibitor of OxPhos identified in-house in collaboration with the Institute of Advanced Cancer Science (IACS)/MD Anderson, causes a metabolic catastrophe in AML subsets and induces profound growth-inhibitory effects in primary CD34⁺ AML cells, with minimal toxicity against normal bone marrow (BM) cells. Preliminary data by project investigators further indicate that resistance to BCL-2 inhibition is associated with altered OxPhos, and that a combination of OxPhos inhibitors and the BCL-2 inhibitor venetoclax is synergistic in parental and in venetoclax-resistant cells. In orthotopic xenografts of primary AML cells, daily dosing with IACS-010759 delayed disease progression, suppressed OxPhos and inhibited hypoxia. A first-in-human Phase I clinical trial of IACS-010759 in AML is ongoing at MD Anderson (PI-Konopleva), and preliminary pharmaco-dynamic studies indicate reduction of oxygen consumption consistent with on-target activity. In this proposal, the investigators will leverage the expertise of the drug discovery unit at MD Anderson with the PI’s extensive focus on tumor metabolism and experience with in-depth analyses of primary patients-derived AML tumors using a battery of cellular, biochemical and genetic methodologies. They will establish combinations of the OxPhos inhibitor with standard chemotherapy and with the BCL-2 inhibitor, venetoclax. The central hypothesis is that key metabolic dependencies of the leukemia and leukemia-initiating cells, such as oxidative phosphorylation, affect leukemia survival and chemosensitivity; and that combined blockade of mitochondrial respiration by OxPhos and BCL-2 inhibitors will eliminate leukemia-initiating cells and enhance anti-leukemic efficacy. To test the hypothesis they propose the following Specific Aims:

Specific Aim 1. Characterize molecular subsets of AML that depend on OxPhos for survival, and examine the combined efficacy of IACS-010759 with BCL-2 inhibitor venetoclax.

Translational goal. To examine sensitivity and RNA signatures of the genomically defined AML subsets (primary AML samples in vitro), and investigate molecular mechanisms of synergy between OxPhos inhibition and BCL-2 blockade

Specific Aim 2. Investigate whether residual AML cells surviving standard chemotherapy or BCL-2 inhibition require OxPhos, and test the impact of IACS-010759 on the residual cells in the in vivo AML PDX models.

Translational Goal. Based on pre-clinical data, optimize the sequential administration of a combination of OxPhos and BCL-2 inhibition or standard chemotherapy, and characterize biomarkers of response, with the goal of the translation into Phase I clinical trials.

Specific Aim 3. Conduct a Phase 1/2 Study of standard chemotherapy and of BCL-2 inhibitor Venetoclax combined with IACS-010759 in patients with salvage 1 or 2 AML.

Translational Goal. The study will pave the way for the future phase II and phase III pivotal combination clinical trials with IACS-010759, with the goal to improve survival in AML.

Introduction of the Co-Project Leaders

The co-project leaders for this project are Giulio Draetta, M.D., Ph.D. and Marina Konopleva, M.D., Ph.D. Draetta is Senior Vice President, Chief Scientific Officer, Professor in Genomic Medicine at MD Anderson. He has spent many years in both academia and the pharmaceutical industry, where he led drug discovery research in Oncology. Konopleva has extensive experience in apoptosis, hypoxia, metabolism and leukemic microenvironmental research.

Translational Relevance

The project proposes to develop a novel therapeutic strategy targeting oxidative phosphorylation (OxPhos) in AML. Project investigators had previously shown that AML cells are unique in their mitochondrial characteristics and have an increased reliance on oxidative phosphorylation. AML cells including LSCs, unlike normal cells, overexpress the anti-apoptotic BCL-2 protein and are unable to upregulate glycolysis sufficiently after OxPhos is inhibited. This unique metabolic and mitochondrial biology makes AML vulnerable to strategies that target OxPhos and BCL-2. Inhibition of cellular respiration with IACS-010759, a novel inhibitor of OxPhos, developed in-house, causes a metabolic catastrophe in subsets of AML and induces profound growth-inhibitory effects in primary CD34⁺ AML cells, with minimal toxicity against normal bone marrow (BM) cells. Preliminary data by project investigators indicated that resistance to BCL-2 inhibition was associated with altered OxPhos, and that the combination of the OxPhos inhibitor and the BCL-2 inhibitor venetoclax was synergistic in parental and in venetoclax-resistant cells. They showed in orthotopic xenografts of primary AML cells that daily dosing with IACS-010759 was well tolerated, suppressed OxPhos and extended survival in mice with human AML patient-derived xenografts (PDX), reducing phenotypically-defined LSC fractions measured by the “next-generation” technique of mass cytometry (CyTOF). They are currently conducting a first in-human phase I clinical trial of IACS-010759 in AML, and preliminary pharmaco-dynamic studies indicate reduction of oxygen consumption consistent with on-target activity, at safe and tolerable doses.

In the SPORE new project, the investigators will combine the expertise of the drug discovery unit at MD Anderson (with extensive focus on tumor metabolism) with their own experience with in-depth analyses of primary patient-derived AML tumors using a battery of cellular, biochemical and genetic methodologies. They will establish pre-clinical combinations of OxPhos inhibitors with standard chemotherapy and with the BCL-2 inhibitor venetoclax. The central hypothesis is that key components of AML, such as metabolic dependence of leukemia-initiating cells on OxPhos, affect leukemia survival and chemosensitivity, and that combined blockade of mitochondrial respiration by OxPhos and BCL-2 inhibitors will eliminate leukemia-initiating cells and produce significant anti-AML activity. These studies will pave the way for the future combination clinical trials with IACS-010759, with the goal to improve survival in patients with AML. The Project Aims are: 1) Characterize molecular subsets of AML that depend on OxPhos for survival, and examine combined efficacy of IACS-010759 with the BCL-2 inhibitor venetoclax. 2) Test the hypothesis that residual AML cells surviving standard chemotherapy or BCL-2 inhibition require OxPhos for survival, and study the impact of IACS-010759 on these residual cells in in vivo AML PDX models. 3) Conduct a phase I-II study of the combinations of the OxPhos inhibitor IACS-010759 with the BCL-2 inhibitor venetoclax, and with standard anti-AML chemotherapy in patients with relapsed/refractory AML.

If successful, the project will result in a novel therapy targeting the unique metabolism of AML cells and may benefit a subset of patients who are highly resistant to current standard chemotherapy.

Click the red plus signs to see detailed information on cores within The Joe Moakley Leukemia SPORE.

Marina Konopleva, M.D., Ph.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.

Introduction of the Co-Leaders

The co-leaders of this core are the two co-leaders for the Leukemia SPORE, Marina Konopleva, M.D., Ph.D., and Jean-Pierre Issa, M.D. Konopleva is a distinguished physician-scientist with a strong record of translational research and developmental therapeutics in leukemia. 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.

Steven Kornblau, M.D.
Leader

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

Carlos Bueso-Ramos, M.D.
Co-Leader

The primary objective of the MD Anderson Leukemia Spore is to improve the treatment of patients with leukemia. A fundamental component to meeting this objective is the conduct of focused translational research involving human tissue and blood specimens, allowing investigation of the biology of target and normal tissues, evaluation of treatment effects on both target and normal tissues, and modulation of relevant biomarkers. To these ends, the Leukemia Sample Distribution, Banking and Array Profiling Core will collect, process and maintain human tissue specimens from patients and will disperse these tissues to Leukemia Spore investigators. The core will also provide genome-wide molecular profiling of RNA and protein expression, which provide insights into cellular physiology such as signaling pathway activity.

The Tissue Procurement and Hematopathology Core has the following objectives:

• Develop and maintain a repository of intact cells, serum, DNA, RNA and protein from blood and bone marrow specimens obtained from AML patients at MD Anderson.
• Maintain a comprehensive, prospective, interactive online database with detailed clinical and pathologic data for the samples received by the core.
• Provide Reverse Phase Protein Arrays (RPPA) from AML patient samples for screening of protein expression in bulk leukemia cells, leukemia stem cells, and mesenchymal stromal cells (MSC).
• Provide RNA-Seq data interpretation for gene expression profiling (GEP).
• Facilitate inter- and extra- Leukemia Spore collaborations through sharing of blood and marrow resources.

Xuelin Huang, Ph.D.
Leader

Xiaoping Su, Ph.D.
Co-Leader

Genesis of the Core

The Biostatistics, Data Management, and Bioinformatics Core for the Leukemia SPORE will be a comprehensive, multilateral resource for data acquisition and management, design of laboratory experiments and clinical trials, development of innovative statistical methodology, statistical analysis, and publishing translational research generated through the Leukemia SPORE.

The core will incorporate sound experimental design principles within all Projects, carry out data analyses using appropriate statistical methodology, and contribute to the interpretation of results through written reports and frequent interaction with Project investigators. The core will provide an integrated data management system to facilitate communication among all Projects and Cores, which will be customized to meet the needs of the Leukemia SPORE and the Department of Leukemia. This process includes prospective data collection, data quality control, data security, and patient confidentiality. Thus, from inception to reporting, translational experiments will benefit from SPORE resources that will be used to augment existing MD Anderson biostatistics resources.

Introduction of the Core Co-Leaders

Xuelin Huang, Ph.D., has a great deal of experience in statistical design and analysis for cancer research. Huang has conducted statistical design for 100+ clinical trials and reviewed 150+ clinical trial protocols. He has published 100+ peer-reviewed statistical methodology and medical collaboration papers, with a primary research focus on survival analysis, especially analysis for recurrent diseases and longitudinal data. Co-director Xiaoping Su, Ph.D.'s research is concentrated on identifying genetic alteration patterns in the cancer genome through integrative analysis of large-scale multi-dimensional genomic data. Su’s specialty has been in the development of robust statistical models and efficient algorithms to detect molecular aberrations including somatic mutations, copy number alterations, transcriptional expression changes, and epigenetic alterations using the next-generation sequencing (NGS) platform. 

Click the red plus signs to see detailed information on programs within The Joe Moakley Leukemia SPORE.

William Plunkett, Ph.D.
Co-Director

Marina Konopleva, M.D., Ph.D.
Co-Director

Genesis of the Program

The success of innovative leukemia translational research is critically dependent on funding for novel and, at times, “high-risk, high-reward” pilot projects that may not be reviewed favorably in mainstream funding venues. Co-led by Marina Konopleva, M.D., and William Plunkett, Ph.D., the Leukemia SPORE Developmental Research Program (DRP) will be a source of seed funding for projects in leukemia to: 1) explore and support innovative leukemia translational research ideas that may mature into full SPORE projects or generate peer-reviewed research grant support, and that may translate into clinically relevant leukemia discoveries; and 2) encourage successful researchers in other fields of research to consider investing their expertise in developing leukemia innovative translational research. Both laboratory and clinical research projects are eligible for funding, provided they are translational in nature. The SPORE DRP has one critical mission: to develop translational research that results in clinically testable hypotheses that might translate into improving the prognosis of patients with leukemia.

Introduction of the Directors

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

Marina Konopleva, M.D., Ph.D.
Co-Director

William Plunkett, Ph.D.
Co-Director

Genesis of the Program

While training in hematology-oncology fellowships and early oncology careers often emphasizes expertise in clinical care and conduct of clinical trials, most of the recent progress in cancer research is derived from deciphering the molecular pathophysiologies of cancers and their microenvironments, identifying selective targets, and developing novel targeted and immunotherapies. Thus, a mentorship program offering well-balanced career development opportunities in basic, translational and clinical research offers new generations of cancer researchers the opportunity to discover different passions and make significant contributions to this burgeoning field. The Career Enhancement Program (CEP) provides an intensive career development for highly talented young investigators, or those established investigators who wish to explore a new career direction, under the robust mentorship of internationally known leukemia experts. The CEP aims to provide structured mentorship opportunities, expert guidance and dedicated time for competitively selected academic physician-scientists, clinician-investigators, and laboratory-based scientists to explore the full spectrum of leukemia translational research.

Introduction of the Directors

Marina Konopleva, M.D., Ph.D., and William Plunkett, Ph.D., serve as co-directors of this program. Konopleva is a well-known physician-scientist whose expertise is in leukemia developmental therapeutics. 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.