TAMI-63. INHIBITION OF LINEAGE STATES WITHIN GBM OVERCOMES CHEMO-RESISTANCE

Abstract

Abstract OBJECTIVE Novel insights into the developmental trajectory exhibited by glioblastoma (GBM) have shown that it has the capability to respond to its microenvironment by clonal selection of specific transcriptional phenotypes. Using the same mechanisms, malignant GBM develop intrinsic mechanisms to resist chemotherapeutic treatments. In this study, we determine the role of the metabotropic glutamate receptor 3 (mGluR3) in chemoresistance and show that inhibition of mGluR3 leads to significant loss of tumor growth volume when concomitantly treated with Temozolomide. METHODS Transcriptomic analysis was carried out post mGlur3 receptor inhibition using LY341495 (100nM), to study loss of transcriptional programs. Morphological and cellular kinetic analysis was carried out post inhibition, to determine apoptosis/necrosis rate, when combined with Temozolomide. The efficacy of the treatment within a human like environment was assessed using our novel human cortical GBM model. RESULTS We present transcriptional and morphological evidence that mGluR3 inhibition using LY341495 leads to loss of both lineage (FDR< 0.01) and reactive (FDR< 0.01) transcription programs. This leads to a loss of ability to evade cytotoxicity when combined with Temozolomide treatment, validated using kinetic apoptosis (p< 0.01). When our cortical GBM model was used to study the effect of treatment within the appropriate microenvironment, we see that the combination therapy leads to a significant reduction in tumor growth (p< 0.01) over the course of 10 days. CONCLUSION Through the integration of diversified molecular-biological analyses, we illustrate a new picture of how glutamate signaling via mGluR3 interacts with phenotypical GBM transcriptional programs to evade effective therapy, the inhibition of which leads to loss of chemo-resistance.