NQO1/SLC711A Assay, Total RNA isolation and running custom TaqMan cards (TLDA) assay on up to 486 PAXgene Blood RNA Samples

Leidos Biomedical Research, Inc., Frederick MD

Investigators

Abstract

NCI Protocol(s): 10247 ?A randomized phase II trial of pevonedistat with Azacitidine versus Azacitidine in adult relapsed or refractory acute myeloid leukemia?; 10249 ?Ixazomib and Pevonedistat in Relapsed/Refractory Multiple Myeloma Patients: A Phase Ib Trial?; 10246 ?Pevonedistat and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome?; 10266 ?A Phase 2 Study of Pevonedistat in Combination with Carboplatin and Paclitaxel in Advanced NSCLC Previously Treated with Immunotherapy?; ADVL1712 ? ?A Feasibility Trial of Pevonedistat Given in Combination with Azacitidine, Fludarabine, and Cytarabine, in Children, Adolescents, and Young Adults with Relapsed or Refractory Acute Myeloid Leukemia? NAE activates the ubiquitin-like protein NEDD8 for conjugation to CRLs and, therefore, regulates the proteasomal destruction of CRL substrate proteins. NAE inhibition prevents degradation of CRL substrates (e.g., NRF2, CDT1), leading to their accumulation. To develop a pharmacodynamic assay, Walker et al. (2011) developed a RT-PCR-based assay using blood samples from multiple healthy volunteers that were treated ex vivo with a range of MLN4924 (pevonedistat) concentrations. Eight genes (including the NRF2-regulated genes NQO1 and SLC7A11) displayed a robust induction (>3-fold) in whole blood. This assay is aimed at assessing whether MLN4924 target engagement, as measured by increased NRF2-regulated NQO1 and SLC7A11 gene expression in whole blood by RT-PCR, is a biomarker of MLN4924 activity.