Last Updated: 09/13/10
The University of Texas M.D. Anderson Cancer Center Leukemia SPORE
Jean-Pierre Issa, M.D., Principal Investigator:
U.T. M.D. Anderson Cancer Center
Department of Leukemia
1515 Holcombe Blvd., Unit 428
Houston, Texas 77030
713-745-2260 tel
713-745-1683 fax
For more information on this specific SPORE's institution, please visit: http://www.mdanderson.org/departments/leukemiaspore/
Leukemia SPOREs
Leukemias are heterogeneous hematologic disorders encompassing acute myelogenous and lymphoid (AML, ALL) and chronic myelogenous and lymphoid (CML, CLL) leukemias, as well as closely related disorders such as myelodysplastic syndrome (MDS) and lymphoproliferative disorders (hairy cell leukemia, mantle cell leukemia, others). A sizable number of people in the United States and worldwide develop leukemias. Despite the fact that major advances in diagnosis and treatment were achieved in the last 50 years, especially in childhood leukemia, this group of diseases remains to be a serious medical problem. According to the American Cancer Society, 59,240 new cases were expected in the United States in 2007. An estimated 21,790 people were expected to die of leukemia in the same year. An interesting decline of incidence and deaths was observed after the mid-1990s with a rate of 3-4% per year. The first round of applications in Leukemia SPOREs took place in the year 2002, with the subsequent establishment of the first Leukemia SPORE in 2003. The second Leukemia SPORE has been established in 2008. This SPORE was named in honor of the late congressman Joe Moakley.
Overall Abstract
The University of Texas M.D. Anderson Cancer Center is proposing a Specialized Program of Research Excellence (SPORE) in Leukemia. The primary goal of this Leukemia SPORE is to cultivate and facilitate innovative and significant translational research in the biologic, genetic and clinical aspects of leukemia to improve understanding, therapy, and prognosis. The multidisciplinary group of investigators in the Leukemia SPORE will accomplish this goal through effective integration of laboratory, epidemiologic and clinical investigations. The SPORE is designed with 5 research projects and 3 core resources, as well as programs for developmental research and career development. The research projects are designed to target specific areas important in leukemia.
Project 1 — Epigenetics and epigenetic therapy in AML
Project 2 — Adoptive Cellular Therapy for Myeloid Leukemia
Project 3 — p53 Activation as Novel Therapeutic Strategy for Acute Myelogenous Leukemia
Project 4 — Incorporating FLT3 inhibitors into AML treatment regimens
Project 5 — Development of Sapacitabine Therapy in Leukemias
Core and other resources are:
Core A — Administration
Core B — Pathology and Tissue Core
Core C — Biostatistics and Data Management
Development Research Program and Career Development Program.
Through this leukemia SPORE, our research team will make a significant impact on leukemia prognosis.
PROJECT 1: EPIGENETICS AND EPIGENETIC THERAPY IN AML
PI/Basic Research:
Jean-Pierre Issa, M.D.
Co-PI/Clinical Research:
Hagop M. Kantarjian, M.D.
DNA methylation and associated epigenetic changes lead to functional alterations in pathways that promote neoplastic development. Epigenetic changes have important translational implications. Methylation in neoplastic DNA is relatively easy to measure and can mark specific subsets of patients with unique natural history and/or responsiveness to chemotherapy. 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). In the previous funding period of this grant, we have shown that DNA methylation and associated gene silencing plays two distinct clinically relevant roles in MDS and acute myelogenous leukemia (AML). We have shown that progression in AML (diagnosis to relapse) and in MDS (MDS to AML) is associated with the progressive acquisition of aberrant DNA methylation that then marks a poor overall outcome. Separately and paradoxically, we have identified a DNA hypermethylation signature that characterizes young patients with AML who have a high cure rate following standard cytotoxic chemotherapy. We propose that, like what was observed in other tumors, methylation in this curable subset of AML specifically inactivates genes important to chemotherapy resistance (e.g. DNA repair genes). In parallel, we have demonstrated proof-of-principle for epigenetic therapy with DNA methylation and histone deacetylase inhibitors in myeloid malignancies. We showed in a series of clinical trials that this approach modulates epigenetics in-vivo, which then correlates with responses, and we contributed significantly to the pivotal trial that led to FDA approval of the hypomethylating agent DAC in MDS.
These observations led to the following hypotheses:
DNA methylation profiling identifies a subset of patients with AML who are curable with standard chemotherapy. We further hypothesize that this curability is related to inactivation of drug resistance genes.
Separately, DNA methylation also contributes to clonal evolution in AML, leading to relapses with drug resistant phenotypes. We further hypothesize that DNA methylation inhibition in remission will delay or eliminate clonal evolution and disease relapse in some patients.
Strategies aimed at enhancing pharmacologic epigenetic reactivation will translate into better therapies for myeloid malignancies.
To address these hypotheses, we propose the following specific aims:
Retrospectively and prospectively validate and extend an epigenetic signature of curability in AML.
Analyze the identified methylation signature in a validation cohort of patients with AML treated with chemotherapy on Southwest Oncology Group (SWOG) clinical trials.
Prospectively analyze methylation the identified methylation signature in all newly diagnosed patients with AML entered on frontline chemotherapy trials at MDACC and in the SWOG.
Use methylated CpG island microarrays (MCAM) to identify the full complement of genes hypermethylated in the identified curable subset of AML.
Clinically and functionally validate selected genes from the MCAM experiment.
Translational implications: A validated epigenetic signature that predicts for curability in AML 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.
Conduct a randomized clinical trial of remission maintenance in AML using DAC
Randomly allocate patients with AML who have achieved CR and completed consolidation therapy to either DAC at a standard dose of 20 mg/m2 IV over one hour daily for 5 days or observation.
Analyze DNA methylation by MCAM, bisulfite pyrosequencing and MSP at (i) pre-chemo (diagnosis), (ii) entry into the trial (CR) and (iii) 3-month intervals during the first year. Correlate patterns at diagnosis, at CR, and patterns of change after therapy with CR duration.
Analyze pharmacodynamic endpoints on DAC therapy (global DNA methylation, methylation and expression of P15 and other selected genes pre-treatment, day 5, day 12 and day 28 of the first 2 cycles and correlate with CR duration within the group randomized to DAC.
Conduct a follow-up trial testing combined DNA methylation and histone deacetylase inhibition as remission maintenance in AML.
Translational implications: Relapse after induction remission account 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 benefit from this approach.
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
Develop, characterize, and validate neoplastic cell line models carrying a methylated CMV promoter/Enhanced GFP vector that can be used to screen for drugs and pathways that lead to epigenetic reactivation/hypomethylation.
Use this (these) system(s) to screen for drugs that synergize with hypomethylating agents in activating gene expression.
Use this (these) system(s) to screen siRNA libraries to identify, in an unbiased way, pathways that lead to gene reactivation in neoplastic cells.
Conduct clinical trials in patients with leukemia of combinations of drugs guided by this in-vitro screen, looking for in-vivo validation of enhanced gene reactivation and clinical activity.
Translational implications: 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 leukemia.
PROJECT 2: ADOPTIVE CELLULAR THERAPY FOR MYELOID LEUKEMIA
PI/Basic Research:
Jeffrey Molldrem, M.D.
Co-PI/Clinical Research:
Richard Champlin, M.D.
Co-PI:
Muzaffar Qazilbash, M.D.
The overall goal of our work is to understand mechanisms of T-cell immunity against leukemia and to develop immunotherapy that will enhance (GVL), graft-versus-leukemia, without (GVHD), graft-versus-host disease. We have shown that CD8+ cytotoxic T lymphocytes (CTL), that are specific for MHC-I restricted peptide determinants derived from aberrantly expressed hematopoietic proteins, can selectively kill leukemia but not normal hematopoietic cells. We previously hypothesized that GVL and GVHD could be separated in part based on unique target antigen specificities of the CTL that mediate each of these effects. Results from our recent Phase I/II vaccine trial with one such peptide that we identified earlier as a leukemia-associated antigen (LAA), which we named PR1, showed that we can induce remission in 16 (24%) of 66 patients with AML, CML, or MDS without causing GVHD in patients who received previous SCT. Our pre-clinical and recent clinical evidence support our central hypothesis that GVL can be induced, and GVHD reduced or eliminated, if immunogenic peptide determinants from aberrantly expressed hematopoietic antigens could be identified and if peptide-specific CTL could be induced by vaccination or elicited by ex vivo expansion from healthy donors and adoptively transferred to SCT recipients. Because patients with leukemia are immunocompromised and often have few remaining normal lymphocytes less than one year after transplant, adoptive cell transfer of T-cells from HLA-matched donors offers the potential to selectively convey GVL in the recipient. Historically, the challenges to this approach have been significant, and include the identification of potent GVL antigens, robust methods to rapidly expand antigen-specific CTL ex vivo in sufficient numbers for adoptive cell transfer, and the crucial long-term persistence of antigen-specific CTL in the recipient following cell transfer.
Specific Aims
Specific Aim 1. To determine whether PR1-CTL elicited from healthy donors are more effective CTL compared to those elicited after vaccination, with a repertoire of higher TCR affinity and an increased proportion of CM cells.
Results of our clinical vaccine trial indicate that it is possible to induce immunity to PR1 by peptide vaccination and that PR1 immunity can cause remission of leukemia. The studies in this aim will help to identify the critical components for inducing effective immunity, so that this can be extended to benefit more patients.
Specific Aim 2. To determine the contribution of differences in the extra-cellular and sub-cellular protein localization of PRTN3 and ELA2 on PR1 antigen cross-presentation and the influence on the memory phenotype of PR1-CTL.
Our preliminary data suggests that aberrant subcellular distribution of target antigens can influence whether potent immunity or tolerance develops. By understanding these mechanisms, we will be able to design rational drug combinations such as interferon, co-stimulatory agents, and toll-like receptor agonists that could be combined with vaccination to induce remission in more patients.
Specific Aim 3. To determine whether selectively isolated high affinity TCR peptide antigen-specific CTL can be adoptively transferred to myeloid leukemia patients after T cell-depleted NST to boost GVL and reduce GVHD.
There is a clear need for improving the success rate of allogeneic (SCT) stem cell transplant. The results of this highly translational aim will be directly tested in patients with AML after SCT. The approach is designed to minimize the risk of GVHD and maximize the benefits of GVL by selectively transferring PR1-specific CTL to recipients.
PROJECT 3: P53 ACTIVATION AS NOVEL THERAPEUTIC STRATEGY FOR ACUTE MYELOGENOUS LEUKEMIA
PI/Basic Research:
Michael Andreeff, M.D., Ph.D.
Co-PI/Clinical Research:
Elihu H. Estey, M.D.
The transcription factor and tumor suppressor p53 is the most frequently mutated gene in cancer. Activation of the transcriptional activity of p53 by a variety of stress signals leads to the expression of genes, which may orchestrate growth arrest, apoptosis, or both. In addition, p53 has also been shown to function outside the nucleus as a pro-apoptotic protein by antagonizing the function of Bcl-XL and directly activating bax, or by binding to manganese superoxide dismutase and promoting the formation of reactive oxygen species (ROS). The levels of p53 are controlled by the ubiquitin ligase HDM2 which targets this tumor suppressor protein for proteasomal degradation. Interestingly, mutations in p53 have been found in only a minority of patients with AML, but it has been reported that overexpression of HDM2 may abrogate the function of p53. Indeed, HDM2 overexpression was reported by our group in 53% of AML, and was found associated with unfavorable cytogenetic characteristics and poor prognosis. HDMX, the human homolog of the murine MDM4, also negatively regulates the function of p53, by stabilizing the p53-HDM2 complex and increasing the function of the E3 ubiquitin ligase of HDM2, resulting in degradation of p53. In addition, it inhibits the transcriptional activity of p53 and was found to be associated with poor prognosis in ALL1. The complex interactions between p53, HDM2 and HDMX have recently been reviewed by Wahl who summarized by stating that MDMX regulates p53 activity, while MDM2 mainly controls p53 stability2-5. MDM2, in turn, is inhibited by Arf, which led us to develop the hypothesis that NPM1 mutations, which are very frequent in AML (>50% of diploid cases) result in a cytoplasmic protein (wt NPM1 protein has nucleolar localization) that sequesters Arf, therefore resulting in lack of MDM2 inhibition. Recently, a potent and selective small-molecule antagonist of HDM2, Nutlin 3a (Roche), has been reported to activate the p53 pathway in cancer cells leading to growth arrest and apoptosis in vivo and in vitro6. We have reported that Nutlins potently induce p53-dependent apoptosis in primary leukemia samples and leukemia cell lines with wt p53 7-10. These studies were aided by the excellent collaboration with Roche scientists (in particular with Dr. L. Vassilev). Nutlin activity was positively correlated with baseline HDM2 levels suggesting that the inhibition of HDM2 may offer considerable clinical benefit for the therapy of AML. Based on the availability of Nutlins and, more recently, of another MDM2 inhibitor11 (MI 63, Ascenta), we have developed a translational research program that will answer important questions regarding regulators of p53 in primary AML samples and their ability to enhance (or inhibit) apoptosis induced by HDM2 inhibitors in vitro and in a first-in-man trial in patients with AML.
Therefore, Aim #1 will identify the molecular determinants of HDM2 inhibition in AML cell lines, primary leukemic cells and stem cells, including p53, HDM2, HDMX and pERK. The inclusion of pERK is based on our observation that MAPK signaling regulates nuclear vs. cytoplasmic localization of p53 and that inhibition of pERK strongly enhances the nuclear pro-apoptotic function of p5310. We will utilize newly developed reverse-phase protein arrays (RPPAs), that allow the analysis of protein and phosphoprotein expression in hundreds of primary AML samples and of FACS-sorted AML stem cells in relatively short time (in collaboration with Drs. S. Kornblau, Core B). Mechanistic studies with NPM transfected cell lines will elucidate the role of wt vs. mt NPM1 in the activity of MDM2 inhibitors. Given the importance of AML stem cells for recurrence of the disease, we will also investigate effects of HDM2 inhibition on leukemic (CD34+38-123+) vs. normal stem cells.
Aim #2 will then investigate the hypothesis that the response to standard chemotherapy in patients with AML is modulated by p53 and its regulators. This hypothesis will be tested by RPPA in archived fully characterized AML samples. Furthermore, the hypothesis will be tested that HDM2 inhibition by non-genotoxic small molecules (like Nutlin 3a and MI 63), which we demonstrated to be synergistic with standard chemotherapeutic agents such as Idarubicin, Doxorubicin and Ara-C, is mediated by NOXA, PUMA and BAD, “BH-3 only” proteins induced by p53. In addition, we will test the hypothesis that phosphorylation of p53 on serine 46 occurs preferentially in response to severe genotoxic stress in AML and increases the affinity of p53 for pro-apoptotic target genes. We and others have demonstrated that MDM2 inhibitors induce apoptosis only in cells with wt p53, which is the situation in the vast majority of AML, and the molecular determinants will be identified that regulate sensitivity to MDM2 inhibitors in this setting. However, a recent report described activity of Nutlin 3a combined with genotoxic agents in cells with mutant p53 and proposed the activation of transcription factor E2F1, which is increased by MDM2 inhibition, and promotes expression of pro-apoptotic proteins including NOXA as underlying mechanism12. We confirmed this finding in preliminary experiments and will therefore extend these investigations in order to define mechanisms and efficacy of Nutlin/chemotherapy combinations in cells with mutant p53 as well.
Finally, in Aim #3, we will perform the “first-in-man” Phase I clinical trial of Nutlin 3a (designated “R7112” by Roche Pharmaceuticals) in patients with AML. A clinical protocol has been developed with Roche and will be submitted in Q4 2007 to the FDA, with an expected start date in Q1 2008. Discussions of combination trials with chemotherapy are underway and will be guided by the Phase I monotherapy data. Similarly, a commitment for drug supply and clinical trials has been obtained from Ascenta Pharmaceuticals for MI 63 (see appended letters of collaboration).
These studies will therefore define mechanisms of sensitivity and resistance to MDM2 inhibitors in AML that will guide the development of future clinical trials of mono and combination therapies, perhaps not only in leukemias, but also in solid tumors, with wild-type and mutant p53.
We therefore submit that this proposal develops mechanism-based concepts for an innovative, non-genotoxic, highly targeted novel approach to leukemia therapy, based on a decade of drug development, rapidly improving (though still incomplete) understanding of the mechanisms involved, clinically relevant preclinical data developed by our group, and the fortuitous fact that the majority of AML patients carry blasts with wt p53 and are therefore expected to benefit from this approach.
PROJECT 4: INCORPORATING FLT3 INHIBITORS INTO AML TREATMENT REGIMENS
PI/Basic Research:
Mark Levis, M.D., Ph.D.
Co-PI/Clinical Research:
Donald Small, M.D., Ph.D.
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.
Specific Aim 1: Using blasts and plasma from AML patients treated with FLT3 inhibitors, correlate the clinical responses of those patients with their plasma drug levels, with the degree of FLT3 inhibition achieved, and with the cytotoxic responses of their blasts to the FLT3 inhibitors in model systems.
Hypothesis: Clinical responses will correlate with sustained, effective FLT3 inhibition, which will correlate with higher free levels of drug; short-term, peripheral responses will correlate with cytotoxic effect on bulk cells, while long-term responses will correlate with cytotoxic effect on leukemia stem or progenitor cells.
Translational goal: Establish the degree of FLT3 inhibition necessary for clinical responses, including achievement of complete remission and improvement in survival.
Specific Aim 2: Use in vitro models to determine if more selective FLT3 inhibitors such as KW-2449 or sorafenib in combination with chemotherapy are as effective against FLT3 mutant AML as CEP-701.
Hypothesis: Highly potent, highly selective FLT3 inhibitors, combined with chemotherapy, may offer equal or greater efficacy against FLT3 mutant leukemias with less toxicity.
Translational goal: Identify a FLT3 inhibitor that, when combined with chemotherapy, is more effective at killing leukemia with greater tolerability.
Specific Aim 3: Determine the response of leukemia stem and progenitor cells to CEP-701, KW-2449, and more selective FLT3 inhibitors, alone and in combination with chemotherapy.
Hypothesis: Leukemia stem and progenitor cells will be more resistant than bulk leukemia cells to the cytotoxic effects of FLT3 inhibition. In combination with chemotherapeutic agents, however, FLT3 inhibitors may succeed in maintaining the quiescence of, or even killing leukemia stem and progenitor cells.
Translational goal: Determine if FLT3 inhibition will be useful as maintenance therapy once remission is established.
PROJECT 5: DEVELOPMENT OF SAPACITABINE THERAPY IN LEUKEMIAS
PI/Basic Research:
William Plunkett, Ph.D.
Co-PI/Clinical Research:
Hagop Kantarjian, M.D.
Nucleoside analogues, the most prevalent members of a single class of cancer therapeutics, differ greatly in the means by which they cause cell death after they are incorporated into DNA. Of those active against leukemias, cytarabine, fludarabine, clofarabine and nelarabine cause stalled DNA replication forks, while thiopurines inappropriately stimulate DNA repair mechanisms to toxic levels, and decitabine and azacitidine act through the epigenetic mechanism of hypomethylation. Sapacitabine, the orally bioavailable form of CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine), is a potent cytosine nucleoside analogue with a novel mechanism of action. The design of CNDAC was based on the concept that once its triphosphate is incorporated into DNA, the addition of a subsequent deoxynucleotide would initiate β-elimination, resulting in cleavage of the 3’-5’ phosphodiester linkage and conversion of incorporated analogue to a chain-terminating nucleotide, CNddC. Clinically active in phase I studies, the mechanisms of action of sapacitabine are unique among therapeutic agents as it causes a single strand nick in DNA that is terminated by a nucleotide that cannot be extended and is resistant to repair. Our hypothesis is that sapacitabine will elicit novel pharmacodynamic responses for detecting DNA damage, for repair of the lesions, and for activation of cell cycle checkpoints that will serve as biomarkers to guide clinical development of sapacitabine alone and in combination with targeted inhibitors of these pathways. We will conduct translational studies in primary leukemia cells in vitro and during therapy that will complement and extend ongoing laboratory investigations. The overall goal of our proposal is to develop a thorough understanding of cellular responses to sapacitabine that will identify biomarkers that have prognostic value to optimize patient selection, schedules of administration in the clinic, and to provide rationales for combinations with agents targeted at inhibiting DNA damage sensors, DNA repair mechanisms and dysregulating checkpoint controls. Thus, the scope of the project will include the clinical translation of new agents that target these biological responses to sapacitabine.
A.2. Specific Aims:
- Evaluate pharmacokinetics and pharmacodynamics of sapacitabine during phase I/II clinical trials in patients with relapsed/refractory leukemias. Determine the optimal dose and schedule for subsequent trials. Investigate the accumulation of the active metabolite, CNDAC-triphosphate in leukemia blasts during therapy. Compare the relationship between dose and triphosphate accumulation in primary leukemia cells in vitro and in leukemia cells from patients treated on clinical trials. Seek relationships between triphosphate accumulation, quantitative pharmacodynamic endpoints in clonogenic assays, with clinical response parameters (cytoreduction, remission). Such characterization of the plasma and cellular pharmacology of sapacitabine will provide information essential to the evaluation of single agent trials, and for the design of combination therapies.
- Characterize biomarkers for cellular responses to sapacitabine. Studies in cell lines indicate that sapacitabine causes single strand DNA breaks that are processed into double strand breaks. Cells respond by activating the G2 checkpoint that spares a portion of the population, as determined by clonogenic assays. We hypothesize that quantitation and comparison of these events in primary cells in vitro and during therapy will have value as prognostic biomarkers. We will quantitate the formation of poly(ADP-ribose) as an indicator of cellular responses to single strand breaks, and the phosphorylation of the histone variant H2AX stimulated by double strand DNA breaks as an indication of further processing of the initial DNA damage. We will evaluate increased phosphorylation of Chk1 kinase and Cdc25C, and decreased phosphorylation of histone H3 as markers for G2 checkpoint activation, and relate this to cell death indicators. Finally, increased JNK phosphorylation, which is diagnostic of stress pathway activation, and decreased Akt phosphorylation, a marker of diminished survival capacity, will be quantified. These investigations will identify biomarkers to demonstrate leukemia responses to sapacitabine that will be evaluated for prognostic value in clinical trials.
- Formulate laboratory rationales for clinical translation of mechanism-based combinations of sapacitabine with small molecule inhibitors. Sapacitabine will be evaluated with novel agents in clinical development for mechanism-based interactions aimed at overcoming potential resistance mechanisms: the enhanced DNA repair property of primary tumor cells and the activation of the G2 checkpoint. Because cells activate nucleotide excision repair to excise the DNA chain-terminating analogue, we hypothesize that combining sapacitabine with fludarabine or clofarabine will inhibit the completion of DNA repair processes and increase cell death. Double strand breaks that result from processing of the CNddC-terminated break or from a second DNA replication over a single strand break are detected and repaired by processes that require ATM and DNA-PK, and which activate poly(ADP-ribose) polymerase. We hypothesize that potent and specific inhibitors of these repair enzymes will increase the cytotoxicity of sapacitabine. Finally, several small molecules that inhibit the DNA damage checkpoint Chk1 kinase are now in clinical trials. We will evaluate their abilities to abrogate the G2 checkpoint pathway and the consequences for cell viability. These investigations will provide a mechanistic rationale for the design of clinical trials of the combinations, and for the identification of patients with disease characteristics predictive of response to sapacitabine.
CORE A: ADMINISTRATIVE CORE
Leader:
Jean-Pierre Issa, M.D.
Co-Leader:
Hagop M. Kantarjian, M.D.
Co-Leader:
Elihu H. Estey, M.D.
The purpose of the Leukemia SPORE Administrative Core is to provide leadership and administrative support for Leukemia SPORE activities. The Administrative Core will be responsible for integrating the diverse scientific disciplines into a unified multidisciplinary approach focused on achieving excellence in translational leukemia research.
The specific objectives of the Administrative Core are:
- Oversee all SPORE activities, including Projects and Core support functions
- Ensure compliance with institutional, governmental, and NCI regulations
- Assume responsibility for communications and consultations with the NCI project officer and other NCI staff to ensure timely preparation and submission of reports and publications
- Oversee the fiscal and budgetary activities of the SPORE
- Coordinate data control quality assurance issues in conjunction with the Internal Scientific Advisory Committee and the Biostatistics and Data Management Core (Core C)
- Coordinate activities associated with clinical trials, e.g., designs, approval by regulatory bodies, implementation, and eligibility and assignment of patients to different studies
- Provide oversight and support for the Biostatistics and Data Management Core (Core C) and the Pathology and Tissue Core (Core B)
- Coordinate meetings of the Executive Committee, the Internal and External Scientific Advisory Committees, monthly investigator meetings, quarterly research meetings, lectures, and symposia
- Administer the Developmental Research Program and the Career Development Program
- Administer the activities of the Patient Advocates
- Ensure compliance with and improvement of policies for recruitment of women and minorities
- Coordinate with other Leukemia SPORE programs and investigators, and other organ-site SPORE programs, to promote communications and integration, through sponsoring a yearly SPORE conference, and distribute materials, electronic communications and progress reports
- Organize seminars to bring to M. D. Anderson consultants and speakers with expertise in various clinical and laboratory aspects of leukemia research; sponsor a yearly conference on Translational Research in Leukemia, to which all Leukemia SPORE applicants and awardees are to be invited
- Maintain a Leukemia SPORE website focused on issues in leukemia translational research
CORE B: PATHOLOGY AND TISSUE CORE
Leader:
Steven Kornblau, M.D.
Co-Leader:
Jean-Pierre Issa, M.D.
Co-Leader:
Carlos Bueso-Ramos, M.D., Ph.D.
The primary objective of the M.D. Anderson Cancer Center 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 tissue, and modulation of, relevant biomarkers. The Pathology and Tissue Core will collect, process and maintain human tissue specimens from patients and will disperse these tissues to SPORE 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 and/or in relapse) receiving care or evaluation at M.D. Anderson Cancer Center. Provide comprehensive hematopathologic characterization of blood and marrow samples used in SPORE projects, including specimens from patients entered onto clinical protocols. Distribute tissue specimens to SPORE investigators for analysis and provide expertise in the interpretation of studies performed on tissue sections within SPORE projects
- Provide stock and customized Reverse Phase Protein Arrays to Spore researchers.
- Maintain a comprehensive, prospective interactive database with detailed clinical and pathologic data for patients with leukemia and MDS receiving care or evaluation at M.D. Anderson Cancer Center
- Facilitate inter-SPORE collaborations through sharing of blood and marrow resources
CORE C: BIOSTATISTICS AND DATA MANAGEMENT CORE
Leader:
Donald Berry, Ph.D.
Co-Leader:
Xuelin Huang, Ph.D.
The Biostatistics and Data Management Core for the University of Texas M.D. Anderson Cancer Center 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 program.
The Biostatistics and Data Management Core will incorporate sound experimental design principles within all Projects, will carry out data analyses using appropriate statistical methodology, and will contribute to interpretation of results through written reports and frequent interaction with Project investigators. The Biostatistics and Data Management 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 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 M. D. Anderson biostatistics resources.
To serve all proposed SPORE projects, as well as the Career Development and Developmental Research Programs, the Biostatistics and Data Management Core has the following objectives:
- Provide biostatistical expertise in the design and conduct of laboratory experiments and clinical trials arising from the research proposed in this application.
- Provide statistical analysis and interpretation of all data collected under the SPORE Projects, Developmental Projects, and other Cores.
- Provide reliable data capture and storage functions, user-oriented retrieval capability, and effective mechanisms for ensuring patient confidentiality.
DEVELOPMENTAL RESEARCH PROGRAM
Leader:
Jean-Pierre Issa, M.D.
Co-Leader:
Hagop Kantarjian, M.D.
Innovative translational research in leukemia is critically dependent on the availability of funding for pilot projects. The Leukemia SPORE Developmental Research Program (DRP) will be a source of seed funding with the following goals:
- encourage and explore innovative translational research ideas which focus on leukemia research; and
- encourage successful researchers working in other fields to focus their expertise toward the development of innovative translational projects in leukemia research. Both laboratory and clinical research projects are eligible for funding, provided that they are translational in nature.
The purpose of the SPORE Developmental Research Program is to develop translational research projects that should result in clinically-testable hypotheses aimed at improving prognosis for patients with leukemia. Support of $100,000 from the SPORE and $100,000 from matching institutional support as described in the letter of Institutional Commitment will provide a total of $200,000 per year available through the Developmental Research Program for approximately 4 to 5 projects (approximately $50,000 per project). Funding will be awarded for 1 year; with satisfactory review from the respective advisory committees and progress on the individual projects’ specific aims, the funding could be carried over for an additional year.
The specific objectives of the Developmental Research Program are to:
- Publicize the availability of funds for pilot translational leukemia research studies. Identify through this mechanism innovative projects with significant potential for improving leukemia therapy and prognosis.
- Encourage collaborations of projects with scientists within the SPORE and outside the SPORE.
- Enhance the communication between the SPORE leaders and outside investigators to encourage the development of innovative translational strategies in leukemia.
- Ensure program flexibility so that developmental projects that show promise can be: 1) funded for a second year; 2) encouraged to apply for peer-reviewed funding (i.e. R01); or 3) expanded to become full SPORE projects.
CAREER DEVELOPMENT PROGRAM
Director:
Hagop Kantarjian, M.D.
Co-Director:
Jean-Pierre Issa, M.D.
The goals and objectives of the Career Development Program (CDP) are to provide training and guidance for academic physician-scientists, clinician-investigators, and laboratory-based scientists who want to dedicate their endeavors to leukemia translational research. To achieve these aims, the CDP will follow these objectives:
- Recruit and train physician, scientists, and senior postdoctoral fellows to become outstanding translational investigators in leukemia research;
- Mentor awardees in the latest advances in cancer biology, at both the molecular and cellular level, emphasizing the translational aspects of research;
- Provide environmental and institutional resources that enable the awardees to excel in their respective fields of research as well as train them to be resourceful in the area of project development and scientific discovery;
- Foster professional growth in the area of translational research by encouraging awardees’ participation in seminars, presentations, conferences both within their parent institution and outside in the scientific community.
Leukemia SPORE Investigators:
Issa, Jean-Pierre, M.D.
U.T. M.D. Anderson Cancer Center
Department of Leukemia
1515 Holcombe Boulevard, Unit 428
Houston, Texas 77030
Kantarjian, Hagop, M.D.
U.T. M.D. Anderson Cancer Center
Department of Leukemia
1515 Holcombe Boulevard, Unit 428
Houston, Texas 77030
Andreeff, Michael, M.D., Ph.D.
U.T. M.D. Anderson Cancer Center
Stem Cell Transplantation
1515 Holcombe Boulevard, Unit 448
Houston, Texas 77030
Berry, Donald, Ph.D.
U.T. M.D. Anderson Cancer Center
Quantitative Sciences Division
1515 Holcombe Boulevard, Unit 1409
Houston, Texas 77030
Borthakur, Gautam, M.D.
U.T. M.D. Anderson Cancer Center
Department of Leukemia
1515 Holcombe Boulevard, Unit 428
Houston, Texas 77030
Bueso-Ramos, Carlos, M.D., Ph.D.
U.T. M.D. Anderson Cancer Center
Hematopathology
1515 Holcombe Boulevard, Unit 72
Houston, Texas 77030
Champlin, Richard, M.D.
U.T. M.D. Anderson Cancer Center
Stem Cell Transplantation
1515 Holcombe Boulevard, Unit 448
Houston, Texas 77030
Estey, Elihu, M.D.
U.T. M.D. Anderson Cancer Center
Department of Leukemia
1515 Holcombe Boulevard, Unit 428
Houston, Texas 77030
Huang, Xuelin, Ph.D.
U.T. M.D. Anderson Cancer Center
Biostatistics
1515 Holcombe Boulevard, Unit 1411
Houston, Texas 77030
Kornblau, Steven, M.D.
U.T. M.D. Anderson Cancer Center
Stem Cell Transplantation
1515 Holcombe Boulevard, Unit 448
Houston, Texas 77030
Levis, Mark, M.D., Ph.D.
Johns Hopkins University School of Medicine
1650 Orleans Street
Room 243
Baltimore, MD 21231
Plunkett, William, Ph.D.
U.T. M.D. Anderson Cancer Center
Experimental Therapeutics
1515 Holcombe Boulevard, Unit 71
Houston, Texas 77030
Molldrem, Jeffrey, M.D.
U.T. M.D. Anderson Cancer Center
Stem Cell Transplantation
1515 Holcombe Boulevard, Unit 448
Houston, Texas 77030
Qazilbash, Muzaffar, M.D.
U.T. M.D. Anderson Cancer Center
Stem Cell Transplantation
1515 Holcombe Boulevard, Unit 448
Houston, Texas 77030
Small, Donald, M.D., Ph.D.
Johns Hopkins University School of Medicine
1650 Orleans Street
Room 243
Baltimore, MD 21231
