Cores

Core A: Leukemia Tissue Bank

Project Summary
The ability to successfully translate basic research in leukemia to the clinical setting, as well as to better understand the relevance of observed clinical or population-based phenomena through laboratory-based research, is greatly facilitated by the availability of an extensive repository of tissue samples, with accompanying pathologic and clinical data, procured from leukemia patients. To fulfill this role, Core A will provide 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 already well-established Ohio State University and CALGB Leukemia Tissue Banks (referred to as SPORE LTBs) constitute the backbone of Core A, and contribute crucial experience and infrastructure to this effort. The SPORE LTBs serves as centralized tissue banks of blood and bone marrow specimens, as well as non-leukemic material, procured from leukemia patients enrolled on CALGB or The Ohio State University treatment protocols, and provide these to investigators within and outside of The Ohio State University.

This work will integrate with Cores B (biostatistics) and C (bioinformatics) to maintain a detailed, current database of samples and accompanying clinical information available. Beyond simply serving as a cell repository, Core A will perform regular validation of sample quality, conduct molecular characterizations, and prepare derivatives (protein, DNA, RNA). The availability of this infrastructure for procuring samples, and the large number of samples already in our possession, will greatly facilitate the conduct of the research projects of this SPORE proposal as well as provide an important and widely available resource for extended studies by investigators within this or outside The Ohio State University Leukemia SPORE.

The aims of Core A are:

  1. To provide central collection, processing and a state-of-the-art repository for samples collected from leukemia patients treated on clinical protocols that are relevant to The Ohio State University Leukemia SPORE.
  2. To provide materials from processed clinical samples to interested investigators, within and outside of The Ohio State University Leukemia SPORE, who examine relevant 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.

The effective collection and characterization of leukemia samples by Core A and their provision to SPORE investigators is critical to the success of the research proposed. The infrastructure of this Core A is therefore already in place, and partially supported through NCI funding through both the CALGB and OSUCCC. In this Core proposal, we seek supplemental, and not overlapping, funding for support of the SPORE projects.

Relevance
Biological mechanistic investigations often rely on cell lines or animal models. While these are powerful research tools, validating laboratory findings in human tissue is crucial to understanding their relevance to human disease. This Core will provide 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.

Performance Site Primary Location
The Ohio State University Comprehensive Cancer Center
DUNS: 07-165-0709
300 W. 10th Ave.
Columbus, OH 43210
Franklin County, United States
Performance Site Congressional Districts: 15

Personnel
Gerard Lozanski, MD, Core Leader
Donna Bucci, Laboratory Manager

Core B: Biostatistics

Project Summary
The principal objective of the Biostatistics Core will be to provide project investigators a centralized resource for statistical expertise. Statistical issues will be addressed at all levels of investigation, from the design of experiments to the conclusions drawn from them, and from the maintenance of data quality to the modeling for population studies and trials. In support of this objective, the specific aims of the Biostatistics Core include:

  1. To 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.
  2. To conduct the statistical analyses of data generated by project investigators, including descriptive summary statistics, data modeling, hypothesis-testing and methods of discovery.
  3. To 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, using randomization of conditions to avoid systematic errors, and decreasing measurement error to enhance precision.
  4. To provide design expertise and oversight for the phase I trials and support the design of possible future phase II trials.
  5. To collaborate with the bioinformatics core for all microarray analyses.
  6. To investigate or develop new statistical methodologies to directly address difficult data or design problems.
  7. To provide design and data analytic support from senior biostatisticians for the new investigators responsible for the pilot projects.

Relevance
The SPORE requires a variety of statistical support, from modeling population-longitudinal data to hypothesis-testing strategies for multiple measures in donor cell experiments. Expertise in experimental and trial design, statistical genetics, multiplicity problems, microarray analyses, and mixed modeling and familiarity with CLL and AML were the requirements used for designing the pool of expertise found in this Biostatistics Core.

Performance Site Primary Location
The Ohio State University Comprehensive Cancer Center,
Center for Biostatistics
DUNS: 07-165-0709
320 W. 10th Ave.
Columbus, OH 43210
Franklin County, United States
Performance Site Congressional Districts: 15

Personnel
Susan Geyer, PhD
David Jarjoura, PhD, Core Leader
Soledad Fernandez, PhD, Co-Investigator
Lianbo Yo, PhD, Co-Investigator
Lai Wei, PhD, Co-Investigator
Xiaoli Zhang, PhD, Co-Investigator

Significant Contributor
Michael Radmacher, PhD, Consultant

Core C: Bioinformatics

Project Summary
The primary objective of the Biomedical Informatics Core is to facilitate the collection, management, integration and analysis of a complete spectrum of information types required for the efficient operation of the SPORE's projects, pilots, and other cores.

Examples of these information types include structured and semistructured data sets resulting from: 1) experimental studies; 2) biostatistical analyses; 3) tissue core and administrative operations; 4) shared resource services; and 5) the asynchronous collaboration of SPORE participants.

We will achieve this objective using a combination of biomedical informatics best practices and advanced technologies already in use or under development within The Ohio State University Department of Biomedical Informatics and The Ohio State University Comprehensive Cancer Center (OSUCCC). Such technologies include: 1) the service-oriented caGrid middleware for electronic data interchange between heterogeneous biomedical data sources and analytical services; 2) advanced database management systems optimized for the storage and query of rapidly evolving biomedical data sets; 3) centralized ontology services and ontology-anchored knowledge discovery/management tools; 4) multiple task-specific Web-portal applications that support the discovery, integration, and analysis of large scale, multidimensional data sets; and 5) Web-based collaborative team-science tools.

We envision the Biomedical Informatics Core as being the central information coordination hub of the SPORE. In order to achieve these objectives, the specific aims of the Biomedical Informatics Core are to:

  1. Develop and support extensible database management systems for use by SPORE participants.
  2. Enable electronic data interchange between SPORE-related data sources.
  3. Support task-specific Web-portal applications that allow end users to discover, integrate and analyze SPORE-related data sources.
  4. Support the execution of SPORE-related clinical trials through the facilitation of access to the OSUCCC's enterprise-grade clinical trials management system.
  5. Implement and support a collaborative Web-portal intended to serve as a medium for both team-science and public dissemination activities.

Relevance
The Biomedical Informatics Core's activities as part of this SPORE will cover a wide spectrum, from the facilitation of high-throughput data analyses to the provision of tools to enable the collaboration of temporally or geographically distributed investigators. As such, the Biomedical Informatics Core will serve as a catalyst for the rapid and efficient conduct of translational studies, with the effect of accelerating the translation and dissemination of basic science discoveries into clinical practice and, ultimately, public-health benefits.

Performance Site Primary Location
The Ohio State University,
Department of Biomedical Informatics
DUNS: 07-165-0709
Street 1: 3190 Graves Hall
Street 2: 333 W. 10th Ave.
Columbus, OH 43210
Franklin County, United States
Performance Site Congressional Districts: 15

Personnel
Philip Payne, PhD, Core Leader
Jeffrey Parvin, MD, Co-Investigator

Core D: Medicinal Chemistry

Project Summary
A major theme of this Leukemia SPORE application is translational research that focuses on identifying therapeutically relevant targets for anti-leukemic drug discovery. Each of the projects presented in this application is a testament to a strong collaborative effort between clinicians and basic scientists, which interfaces many aspects of translational research, including oncogenic signaling, epigenetics, experimental therapeutics and immunology. The Medicinal Chemistry Core integrates the expertise of two laboratories, including medicinal chemistry, molecular and cell biology, and molecular pharmacology (Chen), and computational chemistry and structural biology (Li).

In the past few years, this program has developed a series of agents targeting different molecular defects clinically relevant to leukemogenesis, two of which are ready to enter clinical trials in 2009. Thus, this Core provides a platform to translate basic science findings from each of these projects into the design and synthesis of small-molecule agents for testing individual hypotheses, and adds an important dimension to expedite the translation from bench to the clinic.

Specifically, the following three aims constitute the foci of this Medicinal Chemistry Core, with initial emphasis on targeting immunomodulation in tumor-specific T cells and natural killer cells (Project 3), and protein phosphatase (PP) 2A (Pilot Project 2), which will be expanded to address other new molecular targets arising from other projects. Overall, our specific aims include:

  1. To carry out lead optimization of lenalidomide to develop specific immunomodulatory drugs for chronic lymphocytic leukemia (CLL) therapy (in collaboration with Project 3).
  2. To carry out structural optimization of FTY720 to develop novel PP2A-activating agents (in collaboration with Pilot Project 2).
  3. To 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.

Overall, this unique core will provide members of the SPORE a greater opportunity to translate findings into therapeutic options for patients with leukemia.

Relevance
This Core provides support in synthetic medicinal chemistry and structural biology/computational chemistry to individual projects to translate basic science findings into the design and synthesis of small-molecule agents for hypothesis testing. Lead compounds with therapeutic potential will further undergo structural optimization to develop potent agents for clinical translation.

Performance Site Primary Location
The Ohio State University
DUNS: 07-165-0709
College of Pharmacy, Parks Hall
500 W. 12th Ave. Columbus, OH 43210
Franklin County, United States
Performance Site Congressional Districts: 15

Personnel
Ching-Shih Chen, PhD, Core Leader
Chenglong Li, PhD, Co-Investigator

Core E: Administration

Project Summary
The Administration and Operations Core will provide centralized Leukemia SPORE administration, communication processing, operations oversight, and budget management. This Core will serve to amalgamate the investigators, their experimental findings and ideas, and the evaluation of research efforts, and also to direct the summary efforts toward the Leukemia SPORE outcome. In addition, the Administration and Operations Core will oversee a formal program to enhance woman and minority participation in the scientific programs and also accrual to the proposed clinical trials. This Core will be lead by three experienced researchers in leukemia: Drs. John Byrd, Clara D. Bloomfield and Guido Marcucci.

The Specific Aims of the Administration and Operations Core are:

  1. To 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. This core will provide investigators with clear lines of scientific and administrative communication to promote collaboration among SPORE members, aid in the prioritization of resources, and facilitate timely resolution of program issues.
  2. To organize monthly meetings of the Leukemia SPORE Executive Committee to facilitate effective 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.
  3. To 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.
  4. To organize weekly Leukemia SPORE Project meetings for all SPORE investigators and laboratory members.
  5. To provide overall fiscal review, accounting and real-time budgets analyses for projects, cores, developmental research projects and career development projects within the Leukemia SPORE.
  6. To maintain integration activities that include data sharing, rapid publication, and identification and institution of other novel activities critical to maintaining and strengthening the translational aspects of the Leukemia SPORE as the program develops information, new results and new clinical outcomes.
  7. To 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).
  8. To 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). By pursuing these specific aims, this Administration and Operations Core will provide sufficient support to assure outstanding translational research that facilitates novel discovery to improve risk stratification and treatment options for patients with leukemia.

Relevance
This Core provides administrative support and guidance to all aspects of the SPORE grant.

Performance Site Primary Location
The Ohio State University Comprehensive Cancer Center
DUNS: 07-165-0709
300 W. 10th Ave.
Columbus, OH 43210
Franklin County, United States
Performance Site Congressional Districts: 15

Personnel
John Byrd, MD, SPORE Program Director
Clara D. Bloomfield, MD, SPORE Program Co-Director
LiHui Xu, MD PhD, MBA
Sara Guster, MS, MBA, Core Co-Investigator, Business Manager
Sheryl Baker, BA, Program Accountant

Other Significant Contributors
Cecilia DeGraffinreid, MHS, Operations Associate
Nathan Poeppelman, MS, Opoerations Associate

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) 460 W. 10th Avenue, Columbus, OH 43210 Phone: 1-800-293-5066 | Email: jamesline@osumc.edu