Photo by Einar Fredriksen
A gene expression profiling study has suggested the aurora kinase A (AURKA) pathway may drive graft-vs-host disease (GVHD).
This indicates that AURKA inhibitors, which are readily available in the clinic, might prove useful as GVHD prophylaxis.
Scott Furlan, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers compared the transcriptome of T cells from monkeys with acute GVHD, both treated and untreated for the complication, to healthy controls.
Specifically, the team measured the expression profiles of CD3+ T cells from 5 cohorts of rhesus macaques:
- Allogeneic transplant recipients receiving no GHVD prophylaxis
- Allogeneic transplant recipients receiving sirolimus monotherapy
- Allogeneic transplant recipients receiving tacrolimus-methotrexate
- Autologous transplant recipients
- Healthy controls.
This comparison revealed pathways that were abnormally activated during GVHD in allogeneic transplant recipients receiving no prophylaxis. This included pathways involved in immune signaling, T-cell proliferation, and cell-cycle progression.
Within these pathways were potentially druggable targets that had never before been linked to GVHD.
The researchers said the most notable pathway was AURKA, which controls cell-cycle progression as well cell growth, differentiation, and survival.
When they analyzed tissue samples from transplant patients, the team found that T cells highly expressed AURKA during GVHD.
And in a mouse model of GVHD, a drug targeting AURKA (MLN8237) reduced the severity of GVHD and improved survival. The median survival time was 22.5 days in vehicle-treated controls and 40.5 days in mice that received MLN8237 (P<0.0001).
The researchers said these results suggest that AURKA inhibitors, many of which are commercially available or currently being tested in clinical trials, might help prevent GVHD.
