Further understanding of glioma mechanisms of pathogenesis: implications for therapeutic development

ABSTRACT

Introduction: Recent discoveries in the molecular makeup of gliomas, the relationship of certain molecular drivers, and the patient’s response to therapy and overall prognosis have resulted in a paradigm shift and redefined our understanding of glioma and revealed potential vulnerabilities within this recalcitrant and lethal disease.

Areas covered: We summarize the current classification of malignant glioma in the context of the historical background, current data-driven treatment strategies, and recent discoveries of the mechanisms of pathogenesis of this disease which recapitulates the developing brain. We describe the relationship to common genetic alterations found in glioma, and possible avenues to exploit these newly revealed mechanisms.

Expert opinion: Improved understanding of the molecular underpinnings of this disease has been directly translated into treatment decisions and an improved ability to counsel patients regarding their prognosis. We are beginning to see the first glimmer of a return on the investment in regard to immunotherapy in malignant glioma, with further anticipated successful exploitations of the unique pathophysiology of glioma.

KEYWORDS:

• Glioma
• IDH
• TERT
• 1p/19q
• MGMT
• NLGN3
• tumor heterogeneity
• immunotherapy
• adoptive cell therapy
• CART

Article highlights

• We summarize the current classification of malignant glioma in the context of the historical background, current data-driven treatment strategies, and recent discoveries of the mechanisms of pathogenesis of this disease which recapitulates the developing brain.

• A gain of function mutation in the metabolic enzyme IDH results in the formation of a novel onco-metabolite, 2-HG which interferes with transcription factor binding and disrupts the formation of chromatin loops and physical segregation of DNA, bringing together disparate genetic elements in close physical proximity to influence one another.

• Though the IDH mutation results in a gain of function, the net result is that lower substrate concentrations are available to buffer the oxidizing effect of radiotherapy: NADPH, glutathione, and deoxynucleotides are all reduced in IDH-mutant glioma cells

• IDH-mutated tumors demonstrate defective homologous recombination resulting in increased levels of DNA damage from cellular metabolism as well as alkylating chemotherapy.

• PARP inhibition may be a rational and efficacious strategy in MGMT methylated glioblastoma and IDH mutant gliomas.

• 1p-19q co-deleted gliomas have a decreased ability to produce ultra-long membrane protrusions, termed tumor-associated microtubules (TMs), which appear to be a mechanism of tumor resilience and pathogenesis. TMs enable their host cells to interconnect and form a functional resistance network, conveying resistance to surgical lesions, chemotherapy, and radiotherapy.

• Neoadjuvant pembrolizumab prior to repeat surgical resection may prolong overall survival in recurrent glioblastoma.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.