TMOD-02. IDENTIFICATION OF NOVEL MARKERS OF TREATMENT-REFRACTORY RECURRENT GLIOBLASTOMA
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Abstract Glioblastoma (GBM) is a very aggressive and invasive tumor that relapses within nine months of diagnosis and remains incurable despite advances in multimodal therapy including surgical resection, chemotherapy and radiation. Poor patient outcome has been linked to both marker expression of brain tumor initiating cells (BTICs) and intratumoral heterogeneity (ITH), which have been associated with treatment resistance and tumor recurrence. ITH can be explained at the cellular level by the existence of multiple populations of cancer cells, including some which have acquired stemness properties like self-renewal, proliferation, and multilineage differentiation, also known as cancer stem cells (CSCs). In brain tumors, CSCs or BTICs, have been shown to be resistant to both chemotherapy and radiation treatment, allowing them to escape therapy and consequently allowing for tumor recurrence. As a result, therapies that focus on targeting the BTIC compartment within the bulk GBM tumor would provide better treatment and prognosis for patients. To profile ITH as it evolves through therapy delivery, we have developed a novel and dynamic BTIC patient-derived xenograft (PDX) model of human GBM recurrence, which allows for multimodal profiling of GBM BTICs at engraftment, after chemoradiotherapy delivery in a phase we have termed “minimal residual disease” (MRD), and at tumor recurrence. In this study, we present the profiling of the transcriptome and the cell-surface proteome at each of these stages, including validation of targets, novel and exclusive to recurrent treatment-refractory GBM, by CRISPR/Cas9 knockout and subsequent functional stem cell assays. Despite the fact that recurrent GBM is what ultimately leads to patient demise, it remains a largely unknown landscape. Virtually all of the current genomic, transcriptomic, and proteomic data is based on primary GBM. Hence, our study provides a unique therapeutic window into the often-overlooked elephant in the room: recurrent glioblastoma.
