Research News

Lerner Research Institute has announced the 2019 recipients of the Research Co-Laboratories Award, an internally funded award that encourages "start-up" collaborations and brings together researchers who have not worked together in the past. The award, which provides as much as $100,000 in project funding per year for up to two years, connects those who might not otherwise collaborate to investigate and attack diseases from many angles, drawing on the unique expertise of each researcher. In its second year, the program has now funded five co-laboratories, with three new this year.

Understanding the epigenetics of prostate cancer

Prostate cancer is the second leading cause of cancer-related deaths in the United States. Prostate cancer cells' ability to grow resistant to first-line treatments is the primary reason for this lethality. Once the cells adapt to evade treatment, they grow and spread unchecked.

Hannelore Heemers, PhD, Department of Cancer Biology, and Byron Lee, MD, PhD, Cardiovascular & Metabolic Sciences, are teaming up to find new interventions that may halt this aggressive disease progression. Their collaborative research will focus on activities related to the NKX2-5 gene.

One sign that prostate cells have transitioned from healthy to cancerous is a chemical change, called hypermethylation, to the region of DNA that directs expression of NKX2-5. Changes that affect how a gene functions without actually modifying the gene itself, such as described here, are called epigenetic changes.

Similar to how a light dimmer reduces a light's brightness, hypermethylation turns down NKX2-5 expression. This reduced gene expression results in dangerous changes to the shape and structure of prostate cells that promote aggressive cell behavior and lead to cancer.

With Dr. Heemers' expertise in prostate cancer cell biology and Dr. Lee's in epigenetics, the two will investigate whether restoring normal NKX2-5 function can prevent prostate cancer progression. While most studies into prostate cancer progression focus on genetic targets, this co-laboratory project will focus on epigenetic factors that lead to disease.

Drs. Heemers and Lee are both members of the Cleveland Clinic Genitourinary Malignancies Research Center. Dr. Lee is also a practicing urologist, jointly appointed in the Glickman Urological & Kidney Institute.

Harnessing AI for diagnosing liver cancer

Following immediately behind prostate cancer in terms of cancer-related deaths are liver cancers. As rates of obesity and diabetes continue to rise in the United States, so too has the prevalence of non-alcoholic steatohepatitis (NASH), now the leading cause of liver cancer. Currently, there are no drugs or interventions approved to halt or prevent this lethal progression.

A new research collaboration between Takuya Sakaguchi, PhD, Department of Inflammation and Immunity, and Daniel Rotroff, PhD, Department of Quantitative Health Sciences, will explore how genetics contributes to the progression of NASH to liver cancer. Their investigation will rely on a novel zebrafish model to gain possible insights into disease processes that occur in patients and new therapeutic targets.

Dr. Sakaguchi found a novel genetic mutation in a preclinical model which results in liver inflammation and fibrosis, as commonly seen in NASH patients. Interestingly, unlike other preclinical models, zebrafish have genetic variability and only 60% of the zebrafish with this mutation develop liver tumors, suggesting there is likely some other, currently undefined genetic variant(s) that contribute to liver cancer onset.

The research team will use a genome-wide association study approach to identify new genetic variants associated with liver cancer in zebrafish. Finding these variants is the first step to uncovering new disease-driving genes.

They also seek to develop a predictive model using artificial intelligence (AI) that can analyze histology images to detect early-stage liver cancer and predict treatment response. Incorporating AI into clinical diagnostics has been an emerging interest of the medical community. Drs. Sakaguchi and Rotroff are hopeful that this deep-learning model may one day be used in patient practice.

Combatting transplant-associated pathogens

Transplant patients are particularly susceptible to infections from newly acquired or reactivated pathogens as a result of compromised immune systems. Patients who receive bone marrow or stem cell transplants, technically termed hematopoietic cell transplant (HCT), are particularly at-risk for reactivated human cytomegalovirus (HCMV), a common herpesvirus that lays dormant in 80% of adults, and HCMV-related diseases, which can result in death.

Christine O'Connor, PhD, Genomic Medicine, and Betty Hamilton, MD, Taussig Cancer Institute, are working together to understand how HCMV interacts with transplant patients' immunocompromised systems to spur viral reactivation and infection.

Current HCMV management and treatment interventions target the virus late in its replication cycle. Drs. O'Connor and Hamilton believe therapies should intervene earlier, before it is too late.

In addition to studying host-pathogen interactions, they are in search of biomarkers that can signal which patients are most susceptible to HCMV reactivation and preventive drug targets as there are currently no treatments approved to prevent reactivation. To do so, the researchers will sequence patient and viral genomes to identify proteins and patterns that may help researchers and physicians determine predictive signatures.

Drs. O'Connor and Hamilton will work with and leverage resources from the Cleveland Clinic Blood and Marrow Transplant (CC BMT) Program, including its extensive clinical database and biorepository. Dr. Hamilton is Associate Director of the CC BMT Program.

The power of philanthropy

The Co-Laboratories Award is important not just because it forges new and otherwise unlikely collaborations, but because it makes early state research possible. The seed funding will provide the data researchers need to secure larger funds from external organizations.