Figure 1.

“Window of opportunity” (top row) versus “longitudinal sampling” clinical trial. In the window of opportunity trial (top row), a therapeutic intervention is performed before tumor resection or biopsy. The advantages of this approach are: 1—the therapy can be easily incorporated as part of standard surgery or biopsy; 2—if the surgery is a craniotomy, large amounts of tissue is available for analysis; and 3—relatively simple therapeutic questions can be answered, such as the presence or absence of target engagement. The disadvantages are: 1—only a single timepoint for tissue analyses is available; 2—this timepoint of analysis is early (days to weeks) after the therapeutic intervention; 3—correlations between the therapy’s effect on the GBM (1 timepoint) and biofluid assays (multiple timepoints) must be assumed. In the longitudinal sampling trial, multiple timepoint image-guided biopsies are performed before, during, and/or after the therapeutic intervention. The advantages of this approach are: 1—temporal analyses of therapeutic targets and/or of changes in the TME can be carried out over several weeks to months; 2—temporal correlations between changes in the tumor and in assayed biofluids can be carried out; 3—mechanisms of eventual tumor evasion from the therapy can be understood. The disadvantages of this approach are: 1—the image-guided biopsies are research and not standard interventions and thus the trial can be too expensive for the routine research-based funding mechanisms; 2—there is, albeit low, surgical risk with multiple timepoint biopsies; 3—there can be patient discomfort undergoing multiple procedures over time.