Leukemia SPORE Grant
The Leukemia Specialized Program of Research Excellence (SPORE) grant (CA140158) was awarded to The Ohio State University by the National Cancer Institute (NCI).
Titled “Experimental Therapeutics of Leukemia,” the funding supported five highly translational research projects that were designed to improve understanding of how adult leukemia develops, improve risk stratification and develop novel, individualized therapies for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
The grant also supported five core services, including a Career Development Program geared toward young women and minority researchers, and a Developmental Research Program to recruit innovative pilot projects.
A major thrust of the Ohio State Leukemia SPORE was translating basic-science findings into potential therapeutic targets for anti-leukemic drug discovery, and each project involved clinical and basic-science studies.
The Leukemia SPORE is in the process of submitting a competitive renewal for the next five years of funding. This will present the opportunity for new investigators, projects, pilot projects and scholars to continue the excellent growth set forth by the SPORE grant.
Leukemia SPORE Projects
The Leukemia SPORE grant supported five highly translational research projects that were designed to improve understanding of how adult leukemia develops, improve risk stratification and develop novel, individualized therapies for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
Project 1: Early Predisposing Genes and Risk Stratification for CLL
Project Leaders: Albert de la Chapelle, MD, PhD; John Byrd, MD
Project 1 Aims:
- Extend findings from a co-authored paper published in the journal Cell showing that DAPK1 silencing is associated with CLL development in a family with a high frequency of this disease. This aim investigates the function of DAPK1 in B-cells and the leukemogenic role for DAPK1 silencing in CLL. It’s expected that this work will lead to identification of new biomarkers to predict CLL outcome in Aim 2 and potentially to innovative treatments using novel compounds that could be designed by investigators in Core D.
- Examine the clinical relevance of promoter methylation of genes involved in initiation (DAPK1, FOXD3) or progression (ID4), expression of initiating genes (TCL1A) and other molecular markers (global hypomethylation) with disease progression and clonal evolution.
These investigations should provide a significantly better understanding of early events in CLL transformation and, concomitantly, improve strategies to risk-stratify and treat lgVH unmutated CLL.
Project 2: Molecular Characterization and Risk Stratification of AML
Project Leaders: Clara D. Bloomfield, MD; John Byrd, MD
This study examines whether epigenetic, microRNA and gene expression profiling can predict treatment outcome and identify specific patient groups that will best benefit from targeted therapy in AML. This study examines novel molecular markers, multi-gene expression signatures and multi-microRNA expression signatures in the context of newly diagnosed AML patients enrolled on CALGB clinical trials to facilitate risk-stratified and molecular marker-stratified treatment. Additionally, this project will potentially identify new dysfunctional signaling pathways that are amenable to therapeutic targeting in AML.
Project 3: Lenalidomide As an Immune Modulating Agent for CLL
Project Leaders: John Byrd, MD; Kristie Blum, MD; Amy Johnson, PhD
Project 3 explores the mechanism of action of the unique agent lenalidomide in CLL and seeks to develop new strategies to optimize its efficacy in this disease. Three different lenalidomide studies have demonstrated clinical activity but also the atypical toxicity of tumor flare in CLL patients. To date, the mechanism of action and toxicity of lenalidomide in CLL remains unknown. This project is derived from clinical and laboratory studies published by this group of Ohio State investigators showing that lenalidomide promotes CLL-cell activation and potentially life-threatening tumor flare. Concurrent with ongoing laboratory studies, a phase I clinical trial of lenalidomide will be pursued in patients with symptomatic, previously treated disease and those with minimal residual disease immediately following treatment.
Project 4: Preclinical and Clinical Investigation of MLL-PTD AML
This translational and clinical study investigates epigenetic therapy for a rare subset of AML with MLL-PTD. Dr. Blum explores a discovery made in the laboratory that the well-characterized partial tandem duplication (PTD) of the MLL gene in a single allele occurs in a subset of AML patients. Importantly, the lab also discovered that the wild type MLL allele in this same subset of patients may be silenced by epigenetic regulation, presenting an opportunity for drug-induced re-expression of the gene.
The translational research group at Ohio State has been one of the leaders nationally in developing drugs that target epigenetic changes in leukemic cells. This project will incorporate both preclinical and clinical aims. Notably, creation of a MLL PTD knock-in mouse demonstrated that the lesion described does not alone produce AML. Additional abnormalities such as FLT3 over-expression resulted in development of leukemia in this mouse model. Thus, Project 4 will further characterize/validate and utilize this MLL PTD/FLT3 mouse as a preclinical model and also develop drug treatment strategies targeting epigenetic and genetic aberrations in patients with AML.
Project 5: Preclinical and Clinical Development of Silvestrol in CLL
Project Leaders: Michael Grever, MD
Project 5 focuses on a new therapeutic target that inhibits protein translation, in CLL. This project utilizes the novel natural-product silvestrol that is derived from the Indonesian plant Aglaia foveolata and was identified and characterized in part by Ohio State investigators. Drs. Grever and Lee have been working to translate silvestrol to clinical trials for patients with CLL. It has been shown that silvestrol is selectively cytotoxic toward CLL cells and that the mechanism involves inhibiting the translation of the anti-apoptotic protein Mcl-1.
Ohio State Leukemia SPORE members and others have validated the Mcl-1 target as a critical anti-apoptotic Bcl-2 family member whose reduction directly results in apoptosis in CLL cells. The Leukemia SPORE project team also extended these in vitro studies to show in vivo activity of silvestrol in both the ES-TCL1 CLL model and an alternative lymphoid leukemia xenograft model.
Preliminary pharmacokinetics studies suggest that silvestrol has a relatively short half-life in vivo. To improve the pharmacokinetic parameters of silvestrol, a nanoparticle-encapsulated formulation was developed by Dr. Lee that maintains in vitro activity and will greatly improve the in vivo pharmacology and efficacy. Preclinical studies to test in vivo the toxicity and the pharmacologic activity of silvestrol nanoparticles are ongoing.
Leukemia SPORE Cores
The Leukemia SPORE grant supported five core services, including a Career Development Program geared toward young women and minority researchers, and a Developmental Research Program to recruit innovative pilot projects.
Core A: Leukemia Tissue Bank
Laboratory Manager: Donna Bucci, MS
Validating laboratory findings in human tissue is crucial to understanding their relevance to human disease. Core A provides SPORE researchers with simplified access to a large repository of leukemia patient samples and accompanying clinical information. This multi-tiered effort is essential to the overall goal of this SPORE group to bring their findings to the practical benefit of patients with leukemia.
The core provides researchers in and outside The Ohio State University Leukemia SPORE access to a large repository of uniformly prepared and fully characterized leukemia patient samples. The well-established Ohio State University and CALGB Leukemia Tissue Banks (referred to as SPORE LTBs) are the backbone of Core A and contribute crucial experience and infrastructure to this effort. The SPORE LTBs are centralized banks of blood, bone marrow specimens and non-leukemic material procured from leukemia patients enrolled on CALGB or Ohio State treatment protocols.
Aims of the Leukemia Tissue Bank:
- Provide a state-of-the-art repository and centralized collection and processing, for samples collected from leukemia patients treated on clinical protocols related to The Ohio State University Leukemia SPORE.
- Provide processed clinical samples to investigators within and outside Ohio State’s Leukemia SPORE who study the cellular and molecular properties of leukemia and correlate these properties with clinical or population-based outcomes and who commit to sharing the data derived from their research efforts.
Core A will integrate with Cores B (biostatistics) and C (bioinformatics) to maintain a detailed, current database of samples and accompanying clinical information. In addition, Core A will regularly validate sample quality, conduct molecular characterizations and prepare derivatives (protein, DNA, RNA).
Core B: Biostatistics
Co-Leader: Susan Geyer, PhD
Co-Investigator: Soledad Fernandez, PhD; Lianbo Yo, PhD; Lai Wei, PhD; Xiaoli Zhang, PhD
Significant Contributor: Michael Radmacher, PhD
The Biostatistics Core provides statistical support for the Ohio State Leukemia SPORE. It offers expertise in experimental and trial design, statistical genetics, multiplicity problems, microarray analyses, modeling for population studies and trials and maintenance of data quality.
Aims of the Biostatistics Core:
- Collaborate with project investigators in the formulation of hypotheses and hypothesis-testing strategies and in the design of experiments, phase I trials and population studies.
- Conduct statistical analyses of data generated by project investigators, including descriptive summary statistics, data modeling, hypothesis-testing and methods of discovery.
- Ensure that the following statistical principles are adhered to in all studies:
- Modeling nuisance or block effects
- Controlling type I error to produce reliable conclusions
- Using adequate sample sizes to control type II error and avoid inconsistent conclusions
- Use randomization of conditions to avoid systematic errors
- Decrease measurement error to enhance precision
- Provide design expertise and oversight for phase I trials and support the design of possible future phase II trials.
- Collaborate with the bioinformatics core for all microarray analyses.
- Investigate or develop new statistical methodologies to directly address difficult data or design problems.
- Provide design and data analytic support from senior biostatisticians for the new investigators responsible for the pilot projects.
Core C: Bioinformatics
Leader: Philip Payne, PhD
Co-Leader: Jeffrey Parvin, PhD
The Biomedical Informatics Core facilitates the collection, management, integration and analysis of a wide range of information required for the efficient operation of the SPORE's projects, pilots and other cores. This information includes structured and semistructured data sets resulting from:
- High-throughput and other experimental studies;
- Biostatistical analyses;
- Tissue core and administrative operations;
- Shared resource services;
- The asynchronous collaboration of SPORE participants.
The core uses a combination of biomedical informatics best practices and advanced technologies already in use or under development within Ohio State’s Department of Biomedical Informatics and the OSUCCC – James. These technologies include:
- The service-oriented caGrid middleware for electronic data interchange between heterogeneous biomedical data sources and analytical services;
- Advanced database management systems optimized for the storage and query of rapidly evolving biomedical data sets;
- Centralized ontology services and ontology-anchored knowledge discovery/management tools;
- Multiple task-specific Web-portal applications that support the discovery, integration and analysis of large scale, multidimensional data sets;
- Web-based collaborative team-science tools.
Aims of the Biomedical Informatics Core:
- Develop and support extensible database management systems for use by Leukemia SPORE participants.
- Enable electronic data interchange between SPORE-related data sources.
- Support task-specific Web-portal applications that allow end-users to discover, integrate and analyze SPORE-related data sources.
- Support the execution of SPORE-related clinical trials through the facilitation of access to the OSUCCC – James enterprise-grade clinical trials management system.
- Implement and support a collaborative Web-portal intended to serve as a medium for both team-science and public dissemination activities.
Core D: Medicinal Chemistry
The Medicinal Chemistry Core translates laboratory findings from the Leukemia SPORE research projects into therapeutic options for leukemia patients.
The core provides expertise in synthetic medicinal chemistry and structural biology/computational chemistry and uses it to translate basic-science findings into small-molecule agents for hypothesis testing. Molecules with therapeutic potential are structurally optimized for phase I trial evaluation.
The core integrates the expertise of the Chen laboratory (medicinal chemistry, molecular and cell biology and molecular pharmacology), with the Li laboratory (computational chemistry and structural biology). This program has already developed agents that target different molecular defects that are clinically relevant to leukemogenesis. Two of these agents entered clinical trials in 2009.
Aims of the Medicinal Chemistry Core:
- Carry out lead optimization of lenalidomide to develop specific immunomodulatory drugs for chronic lymphocytic leukemia (CLL) therapy (in collaboration with Project 3).
- Carry out structural optimization of FTY720 to develop novel PP2A-activating agents (in collaboration with Pilot Project 2).
- Provide many aspects of medicinal chemistry service including custom synthesis, sample preparations, computational chemistry and structural biology to interested investigators of this SPORE application (all Projects) and other NCI SPORE and P01 investigators. An example of this is providing OSU-HDAC42 to investigators in Projects 4, 5 and Developmental Project 1.
Core E: Administrative
SPORE Program Director: John Byrd, MD
SPORE Program Co-Director: Clara D. Bloomfield, MD
Core Co-Investigator, Business Manager: Sara K. Guster, MS, MBA
Program Accountant: Sheryl Baker, BA
The Administrative Core provides centralized administration, communication processing, operations oversight, budget management and guidance to all aspects of the Leukemia SPORE grant.
The core promotes collaboration and helps prioritize resources and resolve program issues. It also amalgamates the investigators, their experimental findings and ideas and the evaluation of research efforts. In addition, the Administrative Core oversees a formal program to enhance woman and minority participation in the scientific programs and also accrual to proposed clinical trials.
Aims of the Administrative Core:
- Provide administration and leadership for investigators, including management of project resources, development of critical support memos, recording of meeting minutes and management of communications covering all SPORE operations, including publications.
- Organize monthly meetings of the Leukemia SPORE Executive Committee to facilitate communication and decision-making to accelerate translational research of this organization. This Executive committee shall consist of the Program Director and Co-Directors, Project Leaders, Core Leaders, Executive Advisor, Dr. Carlo Croce and Diversity Enhancement Advisors Drs. William Hicks and Electra Paskett.
- Organize an annual External/Internal Advisory Review meeting where the external and internal panel of experts will assess the Leukemia SPORE effectiveness and experimental progress, research directions, technical approaches, statistical and informatics evaluation and administrative effectiveness.
- Organize weekly Leukemia SPORE Project meetings for all SPORE investigators and laboratory members.
- Provide overall fiscal review, accounting and real-time budgets analyses for projects, cores, developmental research projects and career development projects within the Leukemia SPORE.
- Maintain integration activities that include data sharing, rapid publication and identification and institution of other activities critical to maintaining and strengthening the translational aspects of the Leukemia SPORE as new information, results and clinical outcomes develop.
- Maintain within the SPORE a pipeline of high-quality translational projects via the Developmental Research Program (DRP), with oversight by Drs. Bloomfield and Grever (see DRP write-up for specifics).
- Support a robust Career Development Program (CDP) that is integrated with the mission of the Leukemia SPORE, with oversight by Dr. Bloomfield (see CDP write-up for specifics).
Development Research Program
Project Leaders: Clara D. Bloomfield, MD; Michael Grever, MD
The Development Research Program (DRP) was a critical component of the Leukemia SPORE. It effectively demanded the exploration of new ideas as pilot projects, the development of new resources and the implementation of new technologies that drive translational research.
Aims of the DRP:
- Provide Leukemia SPORE investigators with a source of new projects to replace completed SPORE projects or projects that have not fulfilled translational expectations.
- Fund a broad range of proposals that will enhance existing SPORE Projects, including basic-science investigations, population science; innovative approaches toward prevention, diagnosis and prognosis; and experimental therapeutics.
- Arrange co-mentoring to funded DRP investigators to provide input from basic, clinical and biostatistical leaders and optimize the likelihood of developing the project into a full SPORE project or other nationally funded independent grant.
Career Development Program
Project Leader: Clara D. Bloomfield, MD
The Career Development Program (CDP) was an important component of Ohio State’s Leukemia SPORE and of the national SPORE program because it assured a cadre of academic translational scientists who are dedicated to discovering new approaches to understanding the etiology, epidemiology, prevention, diagnosis, treatment and cure of patients with leukemia.
The goal of the CDP was to recruit, train and guide (i.e., mentor and develop) and retain academic, faculty-level physician-scientists, clinician-investigators and laboratory-based scientists who would dedicate themselves to leukemia translational research.
The program’s success will be judged by the quality of the science generated by the awardees, their success in obtaining external peer-reviewed funding, their success in academic advancement and their retention in academia and leukemia translational research.