While hematopoietic cell transplantation (HCT) is a life-saving therapy for previously fatal malignant and nonmalignant conditions, pulmonary complications such as respiratory failure (RF) remain a barrier. Currently there is no objective way to determine risk of developing RF, thereby limiting opportunities for early intervention and prevention. We have identified 3 biomarkers, including stimulation 2 (ST2, the IL-33 receptor), interleukin 6 (IL-6), and tumor necrosis factor receptor 1 (TNFR1), which hold extreme promise for prognosis of future occurrence of RF when measured as early as day 7 post HCT, well before typical onset of clinical respiratory symptoms. Furthermore, we have conducted the two phases of proteomic discovery using mass spectrometry and have identified 11 additional candidate biomarkers, in addition to ST2, to validate in an independent cohort. Therefore, we hypothesize that prognostic biomarkers can serve as an early warning for the HCT recipient at increased risk for RF.
In Aim 1, we propose to investigate the effect of dynamic changes of validated biomarkers at days 0, 7, 14, and 21 post-HCT on prognosis for RF. We will then, in Aim 2, validate additional diagnostic and prognostic candidate biomarkers for RF discovered through our proteomics pipeline. Finally, in Aim 3, we will conduct a prospective real-time multicenter study to determine RF prognostic biomarkers thresholds for enabling a biomarker-based preemptive trial In addition to elucidating biologic etiologies of RF that could lead to improved targeted therapies, this work will lay the foundation for a biomarker-based preemptive clinical trial aimed to reduce RF and RF-related mortality post-HCT. During the award period, I will conduct research at Indiana University School of Medicine under the primary mentorship of Dr. Sophie Paczesny and the remainder of the co-mentors, advisors and collaborators outlined in the career development plan. I will focus on gaining critical skills in translational research needed to successfully compete for NIH-funding and launch an independent research career. Specifically, I will develop a comprehensive knowledge of clinical biomarker development, proteomic discovery using mass spectrometry, advanced statistical methods to approach biomarker research including prognostic modeling, and skills in implementation science to be able to translate these discoveries into clinical practice. With expertise in acute respiratory failure post-HCT, experience leading multicenter collaborative clinical research studies in this population, and a strong team of mentors and advisors, I am uniquely positioned to successfully complete the proposed study and transition to an independent research career.
Bone marrow transplantation can cure many cancers, blood disorders and metabolic or genetic diseases; however, it can be accompanied by life-threatening pulmonary complications. Respiratory failure can be extremely severe, carries a mortality rate up to 60%, and has little directed treatment outside of supportive care. We propose to study a novel method to predict which patients are at the highest risk to develop respiratory failure using objective biomarkers that may allow for early identification of risk, development of new drugs for respiratory failure based on the biologic pathways identified with biomarkers, and ultimately targeted therapies to prevent the occurrence of respiratory failure.
