A phased, multi-omics liquid biopsy strategy to monitor glioblastoma progression and treatment response
Executive hook: Glioblastoma (GBM) management hinges on timely detection of progression and response to therapy. Non-invasive, longitudinal biomarkers in blood—combining plasma ctDNA, tumor-derived exosomal RNA, and DNA methylation signatures—could offer earlier and more nuanced insights than imaging alone, enabling timely treatment adaptation.
Why this angle matters
- ctDNA in brain tumors is variable but can reflect tumor burden in some patients when present.
- Exosomal RNA can capture tumor-derived transcriptomic signals that may be more stable and informative than free-circulating nucleic acids.
- DNA methylation patterns provide orthogonal tumor biology signals that may enhance detection of residual disease or progression.
- A combined multi-omics panel may overcome the limitations of any single modality and better account for tumor heterogeneity and treatment effects.
Proposed research framework
- Objective: Develop and validate a longitudinal, plasma-based multi-omics panel (ctDNA, exosomal RNA, methylation) to monitor GBM progression and treatment response, aligned to MRI and clinical status.
- Design overview: A phased program starting with discovery in a well-characterized GBM cohort, followed by analytical validation, prospective monitoring, and multi-site validation with governance and ethics oversight.
- Endpoints: Correlation with MRI-defined progression, time-to-progression, treatment response, and potentially health-economic outcomes. Predefined performance targets (sensitivity, specificity, lead time) will be specified before prospective phases.
Evidence plan and phased validation
- Phase 1 (Discovery and feasibility; 6–12 months): characterize detectable signals from ctDNA, exosomal RNA, and methylation in a GBM cohort with serial blood draws and imaging; assess baseline correlations with MRI and clinical status.
- Phase 2 (Analytical validation and panel construction; 12–18 months): develop a minimal robust multi-omics panel with standardized assay workflows; perform cross-validation across archived and prospective specimens.
- Phase 3 (Prospective monitoring pilot; 12–24 months): implement the panel in routine follow-up to monitor progression vs. response, comparing against MRI trajectories and clinical outcomes.
- Phase 4 (Health economics and implementation planning; 12–24 months): evaluate cost-effectiveness, workflow integration, and real-world barriers; outline guidelines for broader adoption.
- Phase 5 (External validation and scale-up planning; 12–24 months): design multi-site validation to confirm generalizability across centers and patient populations.
Implementation, governance, and ethics
- Data governance: obtain IRB approvals, ensure patient consent for serial sampling and data use; implement de-identification and secure data sharing plans.
- Assay standardization: establish standardized pre-analytical and analytical SOPs to maximize inter-site comparability.
- Regulatory considerations: address local/regional regulatory requirements for biomarker tests and potential clinical deployment.
How to contribute
- Share access to well-annotated GBM cohorts with serial blood samples and imaging data.
- Provide input on panel design, endpoints, and acceptable performance benchmarks.
- Engage with clinical and patient-advocacy groups to shape implementation strategies and address patient acceptability.
Timeline overview
- Phase 1: 6–12 months
- Phase 2: 12–18 months
- Phase 3: 12–24 months
- Phase 4: 12–24 months
- Phase 5: 12–24 months
Explicit uncertainties
- This proposal intentionally labels uncertainties (signal prevalence, panel performance, sampling frequency, cost, and regulatory hurdles) to guide iterative refinement as data accrue.