Research News

Lerner Research Institute has announced the formation of three new Centers of Excellence (COE) related to the study of glioblastoma, epilepsy and Alzheimer’s disease. The COE program, which is designed to speed the translation of laboratory discoveries to the patient bedside, provides research teams with $900 thousand in research funding over three years. To help facilitate interdisciplinary and cross-clinic collaboration, each center has two co-directors—one from Lerner Research Institute and one from a clinical institute. Since its creation in 2015, the program has launched 15 centers, with ten still receiving funding.

Center of Excellence in Brain Tumor Research and Therapeutic Development

Glioblastoma (GBM) is the most common primary malignant brain tumor. Unfortunately, GBM uniformly becomes resistant to treatment, which allows the cancer cells to grow and spread. Cleveland Clinic has one of the highest number of active GBM clinical trials in the country, with several of them based on discoveries made in Lerner labs. This center—led by Justin Lathia, PhD, Department of Cardiovascular & Metabolic Sciences, and Manmeet Ahluwalia, MD, Neurological Institute and Taussig Cancer Institute—seeks to leverage these existing collaborations to solidify Cleveland Clinic and northeast Ohio as a hub for brain tumor research.

The center will fund four research projects that seek to overcome the therapeutic resistance commonly associated with GBM by targeting elements of the tumor microenvironment that enable cancer cells to grow and spread. The projects, which are all continuations of previous or ongoing research, will investigate the effects of:

• Differentially targeting subsets of a class of immunosuppressive, pro-cancer cells called myeloid-derived suppressor cells (led by Dr. Lathia)
• Using a drug called ibrutinib to disrupt the blood-tumor barrier, which is a major obstacle to effective therapeutic delivery (led by Shideng Bao, PhD)
• Combining local laser hyperthermia (heat) and radiation to improve the body’s cancer-fighting immune response (led by Jennifer Yu, MD, PhD)
• Targeting oncometabolites found in low grade gliomas to inhibit progression to GBM (led by Thomas McIntyre, PhD)

In addition, the center will facilitate the development and growth of research core services. This includes the development of a core to process and analyze biological samples from multiple clinical trials and the expansion of the tissue core to develop novel models, including patient-derived xenografts and patient-specific organoids.

It will also fund two pilot projects to help generate preliminary data required to obtain larger, extramural funds. These projects will investigate the role of human cytomegalovirus (herpesvirus) in GBM and peptides that may help destroy disease-driving cancer stem cells.

Center of Excellence in Epilepsy and its Comorbidities

Epilepsy is a neurological condition that affects three percent of the U.S. population and is associated with major cognitive and psychiatric comorbidities, increased risk of death and billions in annual healthcare costs. While there are many antiepileptic drugs on the market and surgical therapy is available for drug-resistant epilepsy, current diagnostic techniques make it difficult to discern which patients will be resistant to therapeutics. It is also challenging to predict which drugs have the greatest likelihood of success among those who are sensitive to therapeutics.

The Cleveland Clinic Epilepsy Center is one of the largest, most comprehensive programs in the world for evaluating and treating epilepsy. Under the leadership of Charis Eng, MD, PhD, Genomic Medicine Institute, and Lara Jehi, MD, Neurological Institute, this new center will help build bridges between Lerner researchers and Epilepsy Center physicians.

The center will be organized into four working groups—genomics, preclinical, imaging and clinical—and will fund three research projects, which seek to:

• Identify genetic biomarkers associated with epilepsy, drug resistance, surgery outcomes and comorbidities
• Validate potential biomarkers and therapeutic targets in preclinical models and human tissues
• Develop innovative functional and structural neuroimaging tools to better understand epilepsy brain pathology

To help facilitate these projects and others at Cleveland Clinic related to epilepsy, the center will create new cores and resources, including an epilepsy biorepository with samples from more than 1,000 patients, and purchase new equipment, including an automated blood sampling system and a refrigerated microcentrifuge.

Center of Excellence in Innate Inflammatory Targets for Therapeutic Intervention in Alzheimer’s Disease

Nearly six million Americans live with Alzheimer’s disease, the most common cause of dementia. While there currently are no effective interventions to treat or prevent Alzheimer’s, significant advances have been made in identifying and understanding pathologic hallmarks of the disease, as well as factors that increase disease risk.

One of these factors is genetic variants, including APOE4 (Apolipoprotein E4) and TREM2 (Triggering Receptor Expressed on Myeloid Cells 2), both of which have been implicated to have an inflammatory-related role in Alzheimer’s. This center—led by Tara DeSilva, PhD, Department of Neurosciences, and James Leverenz, MD, Neurological Institute—will foster investigations into APOE4’s and TREM2’s specific roles in Alzheimer’s associated inflammation and potential targets to prevent this disease-driving activity.

The center will fund four projects that aim to:

• Use magnetic resonance imaging to link the genetic markers to white matter lesions associated with Alzheimer’s (led by Dr. Leverenz)
• Use humanized variants in preclinical models to understand how APOE4 and TREM2 affect the activity of microglia, the primary immune cells of the central nervous system, and ultimately disease pathology (led by Dr. DeSilva)
• Discover inflammatory biomarkers associated with Alzheimer’s progression in patients with the genetic variants (led by Lynn Bekris, PhD)
• Develop small molecules that target Alzheimer’s-related immune responses (led by Shaun Stauffer, PhD)

The center will expand Cleveland Clinic’s cohort of patients with APOE4 and various TREM2 variants and continue to collect post-mortem brains from patients with these genetic anomalies. In addition to other databanking efforts, the center will enable cognitive testing among preclinical models of Alzheimer’s.

For more information about the Centers of Excellence program, contact Laura Buccini, DRPH, MPH, at [email protected] or (216) 445-9589.