Co-Leader: John C. Byrd, MD
Co-Leader: Ramiro Garzon, MD
The Leukemia Research Program (LRP), one of five transdisciplinary and highly collaborative research programs at the OSUCCC – James, includes 42 investigators from four colleges and 11 academic departments at Ohio State.
Program members include some of nation’s foremost authorities on science-based treatments for leukemia in its many forms. Their accomplishments over the past several years have elevated leukemia research at Ohio State to international renown.
Areas of strength are: groundbreaking research into the diagnosis and treatment of all forms of leukemia; publishing study results in leading scientific journals, including many with impact factors of 10 or higher; National Cancer Institute (NCI) grant funding of $10.7 million in 2013, a total that constituted 59 percent of all grant funding for this program; a number of large, ongoing, collaborative or network research grants totaling millions of dollars, including an NCI SPORE grant in leukemia, a SCOR grant from the Leukemia & Lymphoma Society for leukemia experimental therapeutics, and several others (listed below).
Some of these large, multi-year, cross-functional grants also support the CLL Experimental Therapeutics Laboratory at the OSUCCC – James. The laboratory conducts translational research efforts and collaborations across the university and the nation to improve understanding of CLL and develop new therapies for this currently incurable disease.
Key Program Objectives
- Examine all molecular aspects of tumor cells—genetic, epigenetic, RNA/protein, non-coding RNAs and biochemical—and integrate these features to improve leukemia risk stratification and more effectively direct targeted therapies toward each person’s unique cancer
- Develop preclinical and clinical immunotherapeutic approaches that bolster the human immune system’s innate ability to combat leukemia
- Devise targeted therapies designed to thwart leukemia-relevant kinase-signaling pathways
NCI Specialized Program of Research Excellence (SPORE): Experimental Therapeutics of Leukemia (P50 CA140158)
Principal Investigator (PI): John C. Byrd, MD Co-PI: Clara D. Bloomfield, MD
Objectives: This grant funds highly translational research that is improving the understanding of leukemia development, risk stratification and therapy. It encompasses five projects involving multiple investigators in acute myeloid leukemia, acute lymphoid leukemia and chronic lymphocytic leukemia.
Leukemia & Lymphoma Society Specialized Center of Research (SCOR): Experimental Therapeutics for Chronic Lymphocytic Leukemia (CLL) (7004-11)
PI: John C. Byrd, MD
Objectives: This grant supports the pursuit of preclinical and clinical investigational multi-targeted therapies for treating genetically high-risk CLL. Investigators in this group have contributed to the clinical development of several drugs now approved or widely used for CLL treatment. Through the SCOR, they have continued to develop therapies for drug-resistant CLL
Blood and Marrow Transplant Clinical Trials Network (U10 HL109322-03) from the National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health
PI: Don Benson, MD, PhD
Objectives: This grant supports The Ohio State Blood and Marrow Transplant Research Consortium, a group of highly experienced transplant centers with a history of collaborating to propose, develop and conduct clinical trials within the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Participating Clinical Centers recruit, examine and treat study participants while also collecting all clinical, laboratory, demographic and other data required by the study. Ohio State, one of several core clinical centers within this network, heads a network consortium that includes Roswell Park Cancer Institute, the University of California at San Francisco Medical Center, the University of North Carolina Hospitals and Virginia Commonwealth
Chronic Lymphocytic Leukemia (CLL) Research Consortium, Project 6
Project Leaders at Ohio State: Carlo Croce, MD
Objectives: Through participation in this consortium, which is funded by the NCI and led by the University of California at San Diego, OSUCCC – James scientists investigate drug resistance in CLL and identify new therapeutic agents.
Phase I Trials of Anticancer Agents (NCI 7 U01 CA076576)
PI: Michael Grever, MD
Objectives: This NCI-funded project conducts correlative phase I studies to evaluate clinical outcomes in the context of basic-science observations. Studies within this project advance new therapies from the bench to the bedside and provide insights into cancer biology.
ITSC for Leukemia: Novel Molecular Strategies for NCTN: Individualized Therapies (CA180861)
PIs: Guido Marcucci, MD; Clara D. Bloomfield, MD
Objectives: This NCI grant supports formation of an Integrated Translational Science Center for Leukemia to support new ideas from outstanding investigators with the goal of revolutionizing leukemia treatment.
NCI’s National Clinical Trials Network (NCTN) – Network Lead Academic Participating Site (U10 CA180850)
PI: John C. Byrd, MD
Objectives: This grant establishes Ohio State as an NCI NCTN—Network Lead Academic Participating Site. The NCTN develops and conducts state-of-the-art cancer treatment and advanced imaging clinical trials, especially large, multi-institutional trials evaluating new cancer therapies and related clinical approaches for adult and pediatric patients. The grant supports OSUCCC – James participation in the NCI-funded clinical oncology cooperative groups.
Translational Training Grant in Experimental Therapeutics (K12 CA133250)
PI: John C. Byrd, MD
Objectives: This grant funds individualized, faculty-level training to ensure a cadre of translational medical doctors and basic science researchers who can collaborate with each other to design and implement hypothesis-driven experimental therapeutic research directed at patients with cancer.
Establishment of an Ohio State University (OSU) human CLL line. Only two true cell lines exist to study chronic lymphocytic leukemia (CLL), and they lack normal control cells to understand the biology of this currently incurable disease. A research team including Albert de la Chapelle, MD, PhD, Carlo Croce, MD, Nyla Heerema, PhD, and others established an OSU-CLL and Normal-CLL line from a patient with CLL by Epstein-Barr virus (EBV) transformation. The patient’s CLL and the CLL cell line derived from it have similar characteristics. The cell line recapitulates CLL in mice. This work, which extends available models for studying gene function in CLL, was published in the journal Public Library of Science One. (PLoS ONE 8(10): e76607).
Senior author: John C. Byrd, MD
Quantitative DNA methylation analysis identifies a single CpG dinucleotide important for ZAP-70 expression and predictive of prognosis in chronic lymphocytic leukemia. Increased cellular expression of the ZAP-70 protein predicts poor prognosis in chronic lymphocytic leukemia (CLL). Because faulty current methods for measuring ZAP-70 expression have prevented widespread application of these tests in clinical decision making, investigators at the OSUCCC – James used DNA methylation profiling of the entire ZAP-70 gene regulatory region to identify sites that are important for transcriptional control. Their work demonstrates the feasibility of using quantitative specific ZAP-70 methylation analysis as a prognostic test in patients with CLL. The findings were published in the Journal of Clinical Oncology (J Clin Oncol 2012 July 10;30(20):2483-2491).
Senior author: John C. Byrd, MD
Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. The treatment for chronic lymphocytic leukemia (CLL) had resulted in few durable remissions before researchers led by the OSUCCC – James conducted a phase Ib-II multi-center study to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of oral ibrutinib, the first drug designed to inhibit a protein called Bruton’s tyrosine kinase (BTK) that promotes the survival and proliferation of CLL cells. The study, published in the New England Journal of Medicine (N Eng J Med July 4 2013.369:32-42), found ibrutinib to be associated with a high frequency of lasting remissions (i.e., a 71 percent overall response) with tolerable side effects in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. This study, along with others at Ohio State and elsewhere, contributed to the February 2014 FDA approval of ibrutinib for treating certain patients with relapsed or refractory CLL.
Co-PI and first author: John C. Byrd, MD