Environment Mediated Drug Resistance in Neuroblastoma
Abstract
During the past three funding years, collaborative experiments have demonstrated that monocytes collaborate with MSC in inducing STAT3-dependent drug resistance in neuroblastoma (Task 1), that S1P/S1PR1 contributes to a sustainable STAT3 activation leading toward increased survival (Task 2), and that Jak2 deletion/inhibition prevents drug resistance (Task 3). Experiments aimed at examining the effect of small pathway inhibitors suggest that inhibition of Jak2, MEK and S1PR1 all contribute to prevent drug resistance, but that inhibition of multiple pathways may be required (Task 4). Experiments aimed at examining the role of IL-6 clearly demonstrate that although IL-6 is involved in STAT3-mediated drug resistance, it is not necessary as STAT3 is activated in IL-6 KO mice and tumors develop in IL-6 KO mice crossed with NB-Tag mice (Task 5). As a result Task 6, which focused on targeting IL-6, has been abandoned. We show in vitro and in neuroblastoma human xenograft models that treatment with FTY720, an antagonist of S1PR1, dramatically sensitizes drug-resistant neuroblastoma cells to etoposide, indicating that S1PR1 is a critical target for reducing both EMDR and acquired chemo-resistance (Task 7).
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2015
- Accession Number
- AD1008813
Entities
People
- Hua Yu
- Yves A. Declerck
Organizations
- Children's Hospital Los Angeles