Unraveling mechanisms of intrinsic resistance

Within the frame of Focus A, (i) patient groups likely to benefit from a molecularly targeted intervention with or without alkylating chemotherapy will be characterized, predictive (longitudinal) biomarkers selected (for primary activity) and prioritized, (ii) a specific emphasis is put on secondary resistance development and novel discoveries are expected (iii) by targeting rhythmic Ca²⁺ activity (KCa3.1) in glioblastoma cell networks in standard co-treatments, as well as (iv) by genetic and pharmacological perturbation of neuro-glioblastoma synases to enhance therapeutic benefit in selected molecularly defined subgroups. Overarching goals of the WPs in Focus A are the development of patient-derived models to define molecular targeted treatments relevant for overcoming glioblastoma-network associated resistance to classical therapies (A01, A06, A07 & A08), specific for H3 (A02) or IDH (A04) mutant subtypes and to generate spatially resolved molecular/imaging maps of primary (A07 & A08) or paired primary-progressive patients-derived samples (A03 & A06). Further, unbiased screening for targets against the network/synaptic structure (A01, A03 & A07), development of combination treatments with temozolomide based on DNA-barcoded small-molecule inhibitors and using iPSC-derived organoids & individualized patient derived organoid (IPTO) model systems (A06 & A08) or treatments other than alkylating agents addressing resistance evolution in glioblastoma a priori unlikely to respond to alkylating treatment (A02, A03) and the clinical implementation of molecular diagnostics from glioblastoma tissue but also cerebrospinal fluid (cell-free DNA and (phospho)proteins) to define trial treatments (A02, A03 & A08).