Dr. Coopersmith and Dr. Ford Receive NIH R01 Grant for Study of Cancer's Effect on Sepsis

June 2013

In 2006, the NIH implemented a multiple principal investigator policy to encourage multidisciplinary efforts and collaboration, particularly in instances where cooperation between equals from different disciplines is the most appropriate way to address a scientific problem. Dr. Craig Coopersmith, an investigator of several ICU-associated issues and associate director of the Emory Center for Critical Care, and Dr. Mandy Ford, a transplant immunologist and assistant professor of the Emory Transplant Center, decided to combine their respective areas of expertise, and have been awarded an NIH Co-PI R01 grant upon first submission for "The Impact of Cancer on the Pathophysiology of Sepsis."

In addition to being the most common comorbidity in septic patients, resulting in nearly 93,000 cases annually, cancer is the comorbidity most associated with septic patient mortality. Dr. Coopersmith's experience studying the consequences of and adaptation to sepsis and shock, and Dr. Ford's focus on examining pathologic immune responses will be applied to defining the possible mechanisms through which pre-existing cancer increases mortality when a host develops sepsis.

"We have created a murine model that replicates the increased mortality seen in septic patients with cancer compared to previously healthy patients who develop sepsis," says Dr. Coopersmith. "Based upon preliminary data, both the immune system and gut integrity appear to be involved, so each of these will be examined in detail."

The co-PIs will perform experiments in multiple models of sepsis with diverse tumor lines to determine if results can be generalized or if they must be separated into specific responses to types of sepsis or types of cancer.

The second goal of the study is to discover why apoptosis prevention—which is widely considered a beneficial therapy for septic patients—turns deadly if sepsis occurs in the setting of cancer. Numerous studies have found that apoptosis prevention in either lymphocytes or the gut epithelium improves survival in previously healthy rodents with sepsis. However, Dr. Coopersmith discovered that when the strategy is used in septic mice with cancer, it markedly increases mortality when applied to lymphocytes, or loses its efficacy when applied to the intestine.

"In the face of current efforts to translate apoptosis prevention to the bedside for treatment of septic patients, the results of this work could potentially change entry criteria and/or prevent inadvertent mortality in patients undergoing clinical trials of apoptosis prevention in sepsis," says Dr. Ford. "We seek to understand a subpopulation within sepsis that may require a different therapeutic approach than the typical septic host, and our conclusions may have significant implications in a disease that is both very common and highly lethal."

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