Case Western Reserve School of Medicine researchers receive NIH grant for four research endeavors

Funding supports research in TB genetics, brain tumor treatment, cancer genetics and the study of ethical and societal issues in human genetic research

Case Western Reserve University School of Medicine faculty members are reaping the rewards of funding from the National Institutes of Health (NIH), in the form of grants and contracts. The funding totals more than $6.4 million for four different research endeavors.

Researchers Mark Chance, PhD, professor of physiology and biophysics, director of the Center for Proteomics and Bioinformatics, and interim chair of the Department of Genetics, and W. Henry Boom, MD, professor of medicine and director of the Tuberculosis Research Unit, are working to tackle the easily transmissible, and often deadly, Mycobacterium tuberculosis (MTB). They received a grant for more than $750,000 from the NIH, with the potential to receive up to $2.8 million over the next four years. The researchers are bringing together a multidisciplinary team of experts in proteomics, genetic epidemiology and cytokine biology to study a population within the spectrum of MTB exposure, infection, and disease in the United States, Uganda, and South Africa, in order to apply novel systems biology approaches to latent infection of the disease.

Recent studies suggest that proteomic approaches aimed at identifying protein-protein interaction networks result in the identification of functional sub-networks with a role in disease pathogenesis. The School of Medicine-led team will apply this approach to the analysis of latent MTB infection in humans and link proteomic results with parallel studies using human genetic and systemic chemo-/cytokine approaches to understanding the disease's pathogenesis.

The Case Comprehensive Cancer Center was awarded a new $2.5 million grant from the National Cancer Institute (NCI) to evaluate the introduction and expression of the modified MGMT gene in hematopoietic stem cells in an effort to improve efficacy of chemotherapy for glioblastoma multiforme (GBM), the most common and most aggressive type of primary brain tumor in humans. The current treatment therapy is hampered by the dose-limiting bone marrow toxicity. This Phase I clinical trial will enable bone marrow to repair DNA alkylation, which is produced by concurrent radiation and temozolomide chemotherapy, by allowing patients to tolerate higher doses of chemotherapy.

This trial will build on the more than two decades of research by Stanton Gerson MD, principal investigator of the study, the Asa and Patricia Shiverick-Jane Shiverick (Tripp) Professor of Hematological Oncology, and director of the NCI-designated Case Comprehensive Cancer Center. He discovered that MGMT gene mutations may protect bone marrow from the drug's toxicity, and in addition, introduction of these mutations can protect viral-transduced cell lines and primary hematopoietic progenitors from chemotherapy-associated toxicity. This trial will be the first-in-man study of in-vivo stem cells selection mediated by a drug resistance gene in patients with GBM. The trial is important not only for GBM patients, but it is also a means to demonstrate the effective development of a platform for selecting gene-modified stem cells that could be used for the correction of numerous monogenic disorders.

In another example of a team science approach, members of the Case Comprehensive Cancer Center have been tapped to join an important NCI multi-site prospective study of all grade II, II and IV glioma patients within the state. With a NIH-awarded contract of $715,000 with the potential for an extension leading to more than $2.5M, researchers will be part of The Cancer Genome Atlas (TCGA) Project, which is a national comprehensive and coordinated effort to accelerate understanding of the genetics of cancer using innovative genome analysis technologies. The overarching goal of TCGA is to improve the ability to diagnose, treat and prevent cancer. Under the direction of principal investigator Jill Barnholtz-Sloan, PhD, assistant professor of general medical sciences, newly diagnosed patients with gliomas will be prospectively accrued from her Ohio Brain Tumor Study (OBTS), a multi-site study within the State of Ohio that includes Case Western Reserve University and University Hospitals (UH) Case Medical Center (the lead site), the Cleveland Clinic Brain Tumor Center, the Department of Neurosurgery at the Ohio State University Medical Center, and the Department of Neurosurgery at the Mayfield Clinic/University of Cincinnati Medical Center.

Case Western Reserve faculty have worked closely with TCGA for many years; Dr. Barnholtz-Sloan and Andrew Sloan, MD, the Peter D. Cristal Chair in Neurosurgery at the School of Medicine and director of the Brain Tumor and Neuro-Oncology Center at UHCMC are active members of the TCGA Glioma Disease Expert Working groups. In this role, they are actively involved in decisions regarding the inclusion criteria for glioma patients and which scientific questions have been prioritized for analysis and publication. In addition, Neal Meropol, MD Chief, Division of Hematology and Oncology, Case Western Reserve University School of Medicine and UH Case Medical Center and Associate Director for Clinical Research, Case Comprehensive Cancer Center is a member of the TCGA Colorectal Cancer Disease Expert Working group.

The Department of Bioethics was awarded a $2.5 million continuation grant from the National Human Genome Research Institute that will extend funding for its Center for Genetic Research Ethics and Law (CGREAL) for an additional four years. The School of Medicine's CGREAL is a national NIH Center of Excellence in Ethical, Legal, and Social Issues (ELSI) Research, which includes more than 20 faculty members across multiple academic departments, clinical units, and institutions in Northeast Ohio. It is co-directed through the collaborative partnership of Patricia Marshall, PhD, professor of bioethics, and Richard Sharp, PhD, director of research in the Department of Bioethics at the Cleveland Clinic. The mission of the CGREAL is to conduct transdisciplinary studies of ethical and societal issues in human genetic research and the introduction of new genetic technologies into patient care and public health; additionally it seeks to prepare young scholars for successful careers in Ethical, Legal, Social Issues (ELSI) research.

In the CGREAL's first five years, it explored a range of ethical, legal and policy issues in the design and conduct of genomic gene-discovery research. In the four years supported by this renewal grant, the center will follow the trajectory of genomics into its "translational" phase, where expanded research needs and higher clinical aspirations are creating new ethical, legal, and policy challenges.