Global Landscape — A Modality-by-Modality Development Map

Building on seed (pre-CC), niche (microenvironment), mobility, plasticity, and composite diagnostics, this chapter surveys GBM development by therapeutic modality. We focus on design logic and clinical pathways rather than exhaustive drug lists.

How to Read This Map

• Targets: Tumor massSeed (pre-CC)Niche (immune/ECM)MobilityBBB/Delivery
• Maturity: Foundation (standard)Extensions (guideline-based/selected)In development (Phase 1–3)
• Assume combinations: optimize single agents → multinode combinations (see Parts 5–6).

Foundation (Standard & Adjacent Extensions)

Surgery, Radiation, Temozolomide Standard

• Maximal safe resection → chemoradiation → maintenance TMZ.
• MGMT methylation aids stratification (Parts 1 & 6).

Tumor Treating Fields (TTF) Extension

• Wear-time adherence is pivotal; combinations explored in selected contexts.

Molecular & Cell-Cycle (Blunting OPC-like “Growth”)

Cell-Cycle Inhibitors

• WEE1 / ATR / CHK1 as radiosensitizers and growth brakes for OPC-like contexts.
• Combination-first logic with radiation and delivery tactics.

EGFR/RTK & PI3K Axis

• Tied to EGFR amplification/variants and PTEN loss (Part 6).
• Heterogeneity/BBB/ plasticity push toward combos rather than monotherapy.

Immune & Niche (Cooling the “Spark” and Suppressive Tone)

Checkpoints & Adjacent Strategies

• Alone: modest; vaccines/oncolytic viruses/local delivery are used to raise the floor.
• Goal: improve antigen presentation and T-cell trafficking.

Myeloid Targets & MIF–CD74

• Reprogram TAMs; restrain suppressive cytokines and niche signals.
• Early “spark” control layered with other nodes (see Part 3).

BBB/Delivery & Locoregional Approaches (“Make It Reach”)

Physical/Mechanical Delivery

• Focused ultrasound for transient BBB opening.
• Convection-enhanced delivery (CED) and catheter-based intratumoral routes.

Nanocarriers & Formulations

• Drug/oligo/protein carriers; imaging-guided localization.

Radiopharmaceutical / Neutron-Dependent Concepts

• Local reaction/energy deposition within tumor regions.
• Eligibility and facility logistics matter; timing with other modalities is key.

Biologic Therapies (Oncolytic Viruses, Vaccines, Cell Therapies)

Oncolytic/Genetic

• Intratumoral delivery to heat up immunity; handshake with checkpoints.
• Focus on spread control, dosing cadence, and safety switches.

Vaccines (Peptide/DC, etc.)

• Toward multi-antigen and personalized designs; composite diagnostics improve matching.
• Coordinate with radiation/locoregional tactics.

Cell Therapies (CAR/TCR, etc.)

• Antigen heterogeneity → multi-target concepts.
• Local or repeated dosing; built-in safety circuits.

Anti-Invasion (ECM/Adhesion/Morphology)

• Target integrins/FAK/Rho–ROCK and MMP/ADAM to narrow routes.
• Base plan is anti-invasion × anti-proliferation (Part 4), plus plasticity-aware layers.

Combination Templates (Examples)

Composite Profile	Main Aim	Supporting Axes
OPC-skew + 7+/10− + EGFR activity	Cell-cycle braking + radiation optimization	Delivery (CED/ultrasound) + niche cooling
MES-skew with tract-aligned spread (DTI)	ECM/adhesion control + anti-proliferation	Immune/myeloid tuning + locoregional
High pre-CC signature + SVZ adjacency	Early seed+niche intervention	Imaging guidance + minimally invasive local therapy

Access & Implementation (Bridge to Part 8)

• Availability of imaging, molecular tests, and delivery devices varies.
• Coverage, trials, and registries shape real-world access.
• Part 8 will map country-specific strengths and practical paths.

Quick Summary

• Global efforts converge on linking growth, niche, mobility, and delivery.
• Composite diagnostics and delivery engineering decide how deep combos can reach.
• Country/center conditions determine which combos are feasible (see Part 8).

My View

To reach deeper with fewer moves, I anchor on delivery and niche cooling, then flank with cell-cycle and anti-invasion. The who/when/what is tuned by composite diagnostics. Next (Part 8), we’ll look at which countries excel at what and how that shapes implementation.

Edited by the Morningglorysciences team.

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