Does Glioma Follow the Brain’s Developmental Blueprint? A Proposal for Ontogenetic Therapy

Is Glioma a Distorted Replay of Brain Development? New Review Ties Treatment to Anatomy

A review published online in the Journal of Clinical Oncology on October 14, 2026 argues that neuroepithelial tumors, which include diffuse gliomas and embryonal tumors, are a distorted and inverted “re-enactment” of how the brain develops. The authors, mostly from University Hospital Zurich, say this view explains features such as cellular mosaicism, spread in preferred directions and treatment-resistant cell states within a single framework. The treatment version of the framework is “ontogenetic multimodal integrated therapy”, which aligns surgery, radiotherapy and drug treatment with the stage of the tumor. This is a review; it does not introduce a new clinical study or drug, and the proposed strategy is not yet a protocol tested in patients. For an overview of brain tumors see our article on brain tumor symptoms, stages and treatment; for current treatments see new treatments for IDH-wildtype high-grade glioma and glioblastoma and where GBM treatment stands.

Why does this matter?

Diffuse gliomas are among the hardest-to-treat brain tumors and can threaten life. In glioblastoma, adding temozolomide to radiotherapy improved survival; even so, 5-year survival was only 9.8% with the drug and 1.9% with radiotherapy alone (Stupp et al., 2009). The absolute difference is about 8 points: the treatment is an advance, but for most patients it is still not enough over the long term.

In recent years molecular diagnosis and targeted drugs have brought real gains for some subgroups. Molecular diagnosis now defines the tumor’s name and treatment options; the FDA has approved vorasidenib for grade 2 gliomas with an IDH1 or IDH2 mutation and dordaviprone for diffuse midline glioma with an H3 K27M mutation. The review’s abstract makes the same point: there has been major progress in diagnosis and there are new targeted therapies for some subgroups, but a unifying framework that integrates cellular hierarchy, spatial heterogeneity and progression patterns is missing.

The authors propose filling this gap with the brain’s own developmental logic. If the tumor is approached by asking “where and in which developmental compartment?” rather than “how big?”, the surgical target, the radiotherapy field and the choice of drug could be tied to the same logic. This is a hypothesis; below we separate what is proposed, what it rests on and what is not yet known.

What is ontogenetic multimodal integrated therapy?

Ontogenetic multimodal integrated therapy is an anatomy-guided strategy proposed by the review. It aims to plan neurosurgery, radiotherapy and drug treatment together according to the tumor’s stage and developmental architecture. The focus shifts from the mass visible on imaging to the tumor’s compartment and developmental logic. It is a testable hypothesis, not a protocol tested in patients.

What exactly does the review argue?

According to the abstract, the authors combine molecular, single-cell, histoarchitectural (the architectural arrangement of tissue) and anatomical observations. They conclude that malignant transformation, aberrant lineage commitment and dedifferentiation mirror and invert physiological developmental pathways. The table below lists the propositions in the abstract and their status.

Cell states and development: what is known in the background?

One of the most concrete observations behind the framework is that glioblastoma cells are not a single type but can shift between states resembling different neural cell types. According to Neftel and colleagues, these states are influenced by the microenvironment, and their proportions differ between tumors. This is one of the biological foundations of the idea of “aberrant lineage commitment and dedifferentiation”; but the observation itself does not prove a treatment strategy.

Why is anatomy at the center of this framework?

The anatomical arm of the review rests on the same group’s 2023 paper in Brain. There, the anatomical patterns of neuroepithelial tumors were found to differ from those of brain metastases and primary central nervous system lymphoma; the tumors showed a hierarchical arrangement following radial units that extend from the ventricle to the brain surface. The authors proposed three anatomical stages for adult-type diffuse gliomas. Because we could not access the full text, we could not verify whether this staging is used unchanged in the JCO review; the diagram below belongs to the 2023 paper only.

In 2023 the authors suggested that surgical targets, biopsy sites and radiotherapy fields could be adapted to the anatomical stage and to the radial unit in which the tumor lies, and noted that multicenter data are needed for this. The JCO review extends this idea from surgery to radiotherapy and drug treatment; the details can only be read in the full text.

What have today’s treatments achieved, and why is a framework needed?

Because the abstract contains no numerical results, here we look at current treatment data that show what the review is trying to move beyond. These are not the review’s findings; they are results of separate studies in different patients and different tumor types.

1. Glioblastoma: adding temozolomide to radiotherapy

This result shows that the treatment works but that long-term survival remains limited. We also covered temozolomide and glioblastoma in our articles on the limits of mouse studies and on a new study on breaking resistance in brain cancer. New approaches in glioblastoma include a personalized peptide vaccine, the SurVaxM vaccine, B7-H3-targeted CAR-T and dual-target CAR-T; none of these is directly related to this review’s proposal, and we give them only as general context.

2. Grade 2 IDH-mutant glioma: vorasidenib

On August 6, 2024, the FDA approved vorasidenib for postoperative use in grade 2 astrocytoma or oligodendroglioma with an IDH1 or IDH2 mutation. The randomized, double-blind, placebo-controlled phase 3 INDIGO trial included 331 patients (vorasidenib 168, placebo 163).

Vorasidenib was associated with increases in liver enzymes: ALT elevation 38.9% versus 14.7%, AST elevation 28.7% versus 8.0%; grade 3 or higher adverse events 22.8% versus 13.5%, discontinuation due to adverse events 6.3% versus 1.2%.

3. H3 K27M-mutant diffuse midline glioma: dordaviprone

On August 6, 2025, the FDA granted accelerated approval to dordaviprone. The indication is adults and children aged 1 year and older with H3 K27M-mutant diffuse midline glioma whose disease has progressed after prior therapy. The basis was a population of 50 patients pooled from five open-label studies without a control arm.

With dordaviprone only 11 patients responded; in 73% of them the response lasted at least 6 months and in 27% at least 12 months. Because there was no control arm, these numbers cannot be compared with placebo or standard treatment. These two examples show that targeted drugs can work in a defined subgroup; the review’s framework aims to combine such treatments with anatomy and developmental logic.

What are the limits of the hypothesis?

• The full text could not be viewed. The comments below rest on the abstract and the group’s earlier work; we could not access the review’s details, diagrams and tables.
• Being a review, it generates no new clinical data. The framework is an interpretation of existing observations; causality between observations is not proven.
• No patient outcome data could be verified. The abstract contains no data showing that anatomy-guided treatment improves survival or quality of life.
• Limit of generalization. The abstract mentions diffuse gliomas and embryonal tumors together; it is not clear whether every subgroup follows the same logic.
• Patient diversity. Brain tumors can behave very differently by age, mutation and location; a single framework may not cover the whole of this variation.

Practical advice for patients and their families

• This review does not describe a treatment or test that can be used today. Do not change your treatment on your own; discuss your questions with your brain tumor team.
• The molecular features of your tumor (such as IDH and H3) determine treatment choice; ask your team which tests were done. Where and how the tumor sits is also important for the biopsy and surgical plan.
• When a decision is difficult, getting a second opinion is reasonable.
• For symptoms such as swelling, seizures and loss of strength, see our articles on brain edema and exercise and rehabilitation; do not take supplements without consulting your team.
• New approaches go through stages of clinical research; for eligible patients, clinical trials can be an option. The first step in humans is usually a phase 1 study.

Frequently asked questions

Does this review present a new glioma treatment?

No. This is a review; it does not introduce a new clinical study or drug, and it proposes a framework for treatment planning. This framework has not been shown to improve outcomes in patients.

Is glioma really a repeat of brain development?

The authors argue this as a way of seeing the disease and base it on molecular, single-cell and anatomical observations. It means tumor cells reflect and invert developmental pathways, but it is not yet a proven rule that explains every aspect of the tumor.

Would this framework change my treatment?

Not at present. Today’s treatment plan is made according to molecular diagnosis, stage and approved options. Whether the framework improves treatment can only be tested in future studies.

Would ontogenetic therapy also change the extent of surgery?

The same group’s 2023 study suggested that surgical targets, biopsy sites and radiotherapy fields could be adapted to the anatomical stage. This is a proposal that needs multicenter validation, so it does not by itself change today’s surgical decisions.

Glossary

Neuroepithelial tumor

The general name for tumors arising from precursor cells of nervous system development; it includes diffuse gliomas and embryonal tumors.

Ontogeny

The developmental process of an organism or organ from conception to maturity; here, the development of the brain.

Diffuse glioma

Glial tumors that grow by infiltrating the surrounding brain tissue and have no clear borders (astrocytoma, oligodendroglioma, glioblastoma).

Embryonal neoplasm

Tumors arising from primitive cells of early development, mostly seen in childhood (for example medulloblastoma).

Dedifferentiation

The return of a mature cell to a more primitive, stem-cell-like state.

Tumor-propagating cell state

A cell state that can help the tumor renew itself and regrow after treatment.