DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (03) Biomarker Discovery and Validation and the specific Challenge Topic, 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases but its clinical utility has been impeded by acute graft versus host disease (GVHD). Unfortunately, the diagnosis of acute GVHD is based on clinical criteria that must be confirmed by biopsy of one of three target organs (skin, gastrointestinal (GI) tract, or liver) due to a lack of a validated diagnostic blood test. We recently reported a four biomarker panel that discriminated between patients with and without GVHD that predicted long term survival independently of GVHD severity. This analysis has been extended to identify biomarkers that specifically predict the future development of GVHD in two major GVHD targets, the skin and the GI tract. In a discovery phase, I used an intact-protein-analysis-system (IPAS) to identify new potential biomarkers present in pooled patient plasma from 10 patients collected 14 days prior to the onset of skin- specific GVHD or GI tract-specific GVHD. I identified 16 candidate proteins that were significantly elevated in the plasma of patients that went on to develop GVHD and that could be readily measured by ELISA assays. During this award period, I propose to validate these candidate GVHD biomarkers in plasma samples from approximately 600 allogeneic transplant patients treated at the University of Michigan since 2000. Furthermore, less than half of patients treated with standard frontline treatment for acute GVHD exhibit complete responses. Therefore, I propose to extend this study to the identification and validation of biomarkers that predict the degree of response to GVHD therapy. Using IPAS, I will identify candidate biomarkers elevated in pooled plasma collected 4 weeks after treatment initiation from therapy-resistant patients but not in the plasma of patients who respond to therapy. I will then validate the candidate biomarkers in plasma samples from approximately 300 matched GVHD patient samples pre-treatment and 4 weeks post- treatment. GVHD pathology not only involves soluble factors but also cellular factors. Therefore, I propose as a complementary and alternative approach, to evaluate cellular biomarkers including levels of regulatory T cells, blood dendritic cells, blood monocytes, and subsets of circulating T cells for their capacity to predict GVHD risk and responsiveness to treatment. Specific aim 1 will validate general, skin, and GI-tract GVHD plasma candidate biomarkers, identify and validate cellular biomarkers, and integrate these findings into a cohesive biomarker panel with the greatest predictive potential for future GVHD occurrence. Specific aim 2 will identify and validate plasma and cellular candidates and integrate these biomarkers into a panel that predicts responsiveness to GVHD therapy. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, acute graft versus host disease (GVHD). Unfortunately there is no validated diagnostic blood test for acute GVHD. Strategies that identify and validate biomarkers of predictive, diagnostic and therapeutic responses for GVHD will allow for better harnessing of treatment in many patients with hematological cancers.
|Effective start/end date||9/30/09 → 8/31/12|
- National Institutes of Health: $500,000.00
- National Institutes of Health: $499,999.00