# Project 2: Biomarkers of endothelial dysfunction in pediatric patients receiving high intensity chemotherapy/irradiation

> **NIH NIH P50** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $202,258

## Abstract

Autologous and allogeneic hematopoietic stem cell transplantation (HCT) are potential curative therapy for
solid tumors and cancers of the blood and bone marrow. However, the efficacy of this procedure has been
impeded by several transplant-related-mortality (TRM) due to complications including complications involving
damage of the endothelium in the really early phase of HCT (day 0 to 14 post-HCT) (1, 2). Sinusoidal
obstruction syndrome (SOS), also called veno-occlusive disease of the liver, is one of these complications of
endothelial origin that appears early after HCT but also other intensive chemotherapy regimen with irradiation
of the abdomen such as in patients with neuroblastoma. Despite its relatively lower incidence in the recent
years due to less aggressive conditioning regimen, the cases of SOS that evolve to multiorgan failure (MOF)
have a mortality rate higher than 80%. Pre-transplant clinical or transplant characteristics have minimal ability
to predict SOS incidence and outcomes. No biomarkers currently in clinical use are suitable for stratifying
patients according to risk of developing SOS. Our objective in this proposal is to validate early biomarkers of
SOS in a prospective multicenter trial for use in a future preemptive trial. Our central hypothesis is that SOS
development can be predicted from analysis of defined biomarkers. This hypothesis is based on our
preliminary data characterizing a panel of three early biomarkers: L-Ficolin, hyaluronic acid (HA), and
suppression of tumorigenicity-2 (ST2) which permit diagnosis of SOS prior to appearance of clinical signs. The
rationale for this study is that once we are able to identify patients who are at particularly high risk for
subsequent SOS; we will propose preemptive, customized treatment plans that could ultimately avert the
development of SOS and improve survival. The hypothesis will be tested through three specific aims: 1) In a
prospective multicenter study including Texas Children, University of Michigan, National Children's, and
Indiana University, evaluate L-Ficolin, HA, and ST2 as early proteomic predictors of SOS to allow future
preemptive intervention with an efficient treatment: defibrotide. 2) Using the same prospective multicenter
cohort as Aim 1, also evaluate responders and nonresponders to defibrotide using our proteomic markers
panel (L-Ficolin, HA, and ST2) as well as with discovery of new markers via our well-established proteomic
workflow. 3) Identify and validate genomics candidate biomarkers of endothelial dysfunction in pediatric
patients receiving high intensity chemotherapy/irradiation using approximately 1000 DNA samples from
patients accrued in our retrospective IU HCT cohort, the multicenter HCT cohort, and this new cohort, the latter
being enriched three times for complications. This approach is significant and innovative because it sets the
grounds for a novel approach to SOS using biomarkers as a guide for starting treatment in a preemptive
man...

## Key facts

- **NIH application ID:** 9974301
- **Project number:** 5P50HD090215-05
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Sophie Paczesny
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,258
- **Award type:** 5
- **Project period:** — → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974301

## Citation

> US National Institutes of Health, RePORTER application 9974301, Project 2: Biomarkers of endothelial dysfunction in pediatric patients receiving high intensity chemotherapy/irradiation (5P50HD090215-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974301. Licensed CC0.

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