EXTH-59. ESTABLISHING GAUSSIA LUCIFERASE REPORTER AS A BIOMARKER FOR ESTIMATING THERAPEUTIC RESPONSE AND PROGRESSION-FREE SURVIVAL IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA

Abstract Serial monitoring of tumor burden in patient-derived xenograft (PDX) models used for testing new cancer drugs via MRI and other imaging techniques can be costly. We theorized that transducing the Gaussia luciferase (GLuc) reporter gene into glioma PDX models (GliomaPDOX) allows for GLuc to be used as a biomarker for tumor burden. This current study investigates whether changes in the rate of GLuc secretion over time (i.e., “growth rate” changes) can predict survival in GliomaPDOX. Optimal cutoff values to define disease progression via GLuc measurements were established resulting in a strong association between progression-free survival (PFS) and overall survival (OS). The pLenti-CMV-sGluc-T2A-EGFP plasmid was packaged into a second-generation lentiviral system via HEK293FT cells, and the resulting virus transduced into directly-isolated glioma patient cells to establish the MGMT-Unmethylated and MGMT-Methylated GliomaPDOX. MGMT-Unmethylated GliomaPDOX were treated with placebo or Temozolomide (TMZ) until endpoint. MGMT-Methylated GliomaPDOX were treated with placebo or TMZ for three weeks or TMZ for six weeks until endpoint. Treatment response was monitored through GLuc measurements obtained via tail blood collection. The optimal cutoff for time to progression was a 30% increase in GLuc, which yielded a significant positive association between PFS and OS across all models and treatments (R2 = 0.8177, p<0.0001). Compared to the MGMT-Methylated placebo and MGMT-Unmethylated groups, the MGMT-Methylated treatment groups exhibited substantial changes in GLuc growth rates and significantly longer PFS and OS (p<0.0001). More specifically, the six-week MGMT-Methylated TMZ-treated group demonstrated a significant difference in GLuc growth rates and a considerable PFS (p<0.0038) and OS increase (p<0.0049) when compared to the three-week MGMT-Methylated TMZ-treated group. Therefore, GLuc measurement is a valuable biomarker for PDX tumor burden and can be used to estimate treatment response and PFS.