Liquid Biopsy in Glioblastoma Treated with Chemoradiation and an Oxygen Therapeutic - HYPOTHESIS AND SPECIFIC AIMS Outcomes for patients with Glioblastoma (GBM), the most aggressive malignant brain tumor in adults, are driven by the genetic underpinning of the tumor, such as methylation status of methyl guanine methyltransferase (MGMT) gene promoter and expression of tumor hypoxia genes. Standard treatment for GBM patients is surgery followed by chemoradiation with routine serial MRI to assess treatment response. After chemoradiation, MR imaging may exhibit increased enhancement that could represent tumor in 30% or more of cases, the phenomenon of pseudoprogression (PsP) from treatment. It is challenging to distinguish between true progression and PsP, so patients and providers need other means to evaluate the disease trajectory. Liquid biopsy is a non-invasive approach to evaluate disease trajectory through tumor genotype and gene expression. GBM is a hypoxic tumor; tumor hypoxia is known to curtail response to chemoradiation. Dodecafluoropentane emulsion (DDFPe) was tested in a Phase IIa trial in association with chemoradiation to treat GBM. DDFPe was well tolerated, showed reversal of tumor hypoxia, and demonstrated improved progression free survival (PFS) and overall survival (OS). Enrollment is underway in a Phase IIb trial testing DDFPe as an oxygen therapeutic (radiosensitizer) in association with chemoradiation treatment in GBM patients. Prior work with DDFPe shows that PsP, in comparison to true progression, on MR imaging is more prevalent after chemoradiation. The hypotheses to be tested in this revised Direct to Phase II SBIR application are as follows: 1) Treatment with DDFPe will alter expression of biomarkers associated with tumor hypoxia and 2) Blood-based biomarkers will enable differentiation of PsP from progressive disease (PD). Thus, our Specific Aims are directed to explore this pivotal observation which is to correlate blood-based biomarkers for hypoxia with radiosensitizer treatment and PsP. FYR Diagnostics will partner with NuvOx to establish liquid biopsy assays that support DDFPe therapeutic product development. FYR will employ a multi-omics approach to discover novel biomarkers utilizing enabling technology to enrich extracellular vesicle (EV) subpopulations in patient blood plasma. Circulating EV biomarkers will aid in identification of patients who may benefit most from radiosensitizer treatment and facilitate monitoring of response to treatment with or without a radiosensitizer. FYR and NuvOx will work synergistically to discover and validate hypoxia biomarkers to create an accompanying companion diagnostic assay to aid in safe and effective use of DDFPe. PsP biomarker development will have massive implications in patient management in the presence or absence of radiosensitizer treatment, ultimately necessitating creation of LDT or IVD assays. This is the first time that liquid biopsies will be studied in GBM in association with a radiosensitizer. We expect to garner valuable insights into gene expression in chemoradiation treatment, signatures to distinguish PsP from PD, and predictive patterns with respect to OS.
