Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is an increasingly common life threatening complication following high dose chemotherapy in children undergoing hematopoietic stem cell transplantation (HSCT). SOS is clinically defined as the triad of weight gain, painful hepatomegaly, and hyperbilirubinemia. The incidence is 10-38% in HSCT patients depending on donor source and preparative regimen with 7% being severe and resulting in greater than 90% mortality by day 100 post-HSCT. Present knowledge suggests that high dose chemotherapy damages hepatic sinusoidal endothelium with activation of inflammatory mediators and initiation of the coagulation cascade resulting in deposition of fibrin evolving to SOS. While coagulation defects have not been identified and the thrombotic process behaves normally, albeit excessively, inflammatory cytokines and other immune targeting proteins produced by endothelial damage activate and drive the development of SOS. This can result in progression to multiorgan failure with a high risk of mortality. In vitro studies have shown that release of SOS-related coagulation factors can be reduced by blocking this inflammatory response to endothelial damage. However, there is little known about the specific inflammatory mediators/biomarkers of the SOS process. In preliminary studies, we collaborated with the University of Michigan to carry out a discovery study for identification of proteomic predictors of SOS. We identified a group of inflammatory and immune cell trafficking proteins that were strongly associated with SOS. We hypothesize that a targeted combination of these biomarkers along with associated genetic changes will help predict an individual patient's risk for developing post-HSCT SOS. We propose to carry out an informed, targeted evaluation of biomarkers of SOS in pediatric HSCT patients, including a focused panel of inflammatory and immune cell trafficking pathway proteomics and genomics. The rationale for the proposed research is that once we understand the relationship of specific biomarkers to HSCT-related SOS in children, we will be able to 1) use specific biomarkers prior to transplant to identify high risk patients for developing SOS and adjust therapy to reduce their risk, and 2) identify target genes/proteins that illuminate the mechanisms of toxicity and that are potential therapeutic targets.
This research is important for improving the effectiveness of anti-cancer drugs to eradicate childhood malignancies and at the same time reduce toxicities of these drugs. This research proposes to combine genetic and proteomic factors together with a child's response to drugs to individually tailor future anti-cancer drug treatments.
|Hennessy, S; Flockhart, D A (2012) The need for translational research on drug-drug interactions. Clin Pharmacol Ther 91:771-3|