H3K27-altered diffuse midline glioma: a paradigm shifting opportunity in direct delivery of targeted therapeutics

Abstract

Introduction: Despite much progress, the prognosis for H3K27-altered diffuse midline glioma (DMG), previously known as diffuse intrinsic pontine glioma when located in the brainstem, remains dark and dismal.

Areas covered: A wealth of research over the past decade has revolutionized our understanding of the molecular basis of DMG, revealing potential targetable vulnerabilities for treatment of this lethal childhood cancer. However, obstacles to successful clinical implementation of novel therapies remain, including effective delivery across the blood-brain barrier (BBB) to the tumor site. Here, we review relevant literature and clinical trials and discuss direct drug delivery via convection-enhanced delivery (CED) as a promising treatment modality for DMG. We outline a comprehensive molecular, pharmacological, and procedural approach that may offer hope for afflicted patients and their families.

Expert opinion: Challenges remain in successful drug delivery to DMG. While CED and other techniques offer a chance to bypass the BBB, the variables influencing successful intratumoral targeting are numerous and complex. We discuss these variables and potential solutions that could lead to the successful clinical implementation of preclinically promising therapeutic agents.

Keywords: Diffuse midline glioma; H3 K27-altered; H3 K27M; blood–brain barrier; convection-enhanced delivery; diffuse intrinsic pontine glioma; pharmacokinetics; targeted therapeutics.

Figure 1.. Location and implicated anatomy of H3K27-altered diffuse midline glioma (DMG).

(a) DMG tumors were traditionally believed to be pontine, as indicated on the (Ai) sagittal T1 and (Aii) axial T2 MRIs. However, improvements in imaging, biopsy and molecular biology revealed these tumors throughout the midline structures including the thalamus, midbrain, pons, medulla, cerebellar peduncles, and cerebellum. These regions (black dashed line) can be appreciated on both sagittal (Ai) and axial (Aii) planes. (b) The diffuse nature of DMG brainstem gliomas has the potential to impact important neurological structures. (Bi) Projection fibers carrying information from the spinal cord must pass through the midline structures to reach the cortex and may be disrupted by tumor infiltration. (Bii) Additionally, cranial nerves and other nuclei located as displayed by the cross-section can be disturbed by the tumor causing malfunction. Figure created in BioRender.com.

Figure 2.. Implications for direct intratumoral targeting of H3K27-altered diffuse midline glioma.

(a) The delicate location within the brainstem and intact blood–brain-barrier (BBB) eliminates surgical intervention and limits systemic therapeutic efficacy. Delivering therapy directly to the brainstem tumor via an implanted catheter has the potential to enhance therapeutic benefit. (b) The variable impacting the potential success of intratumoral targeting are complex and multifold. First, targeted therapies with significant therapeutic potential must be identified by in vitro drug screens and dose-response analysis. Furthermore, intratumoral targeting is dependent on inherent physicochemical properties of the drug itself such as solubility, lipophilicity, molecular and/or the physicochemical properties of the drug packaging, like a nanoparticle. Finally, successful delivery will require optimization of the delivery technique itself. This might include such things as infusion rate, catheter design, or trajectory planning. Figure created in BioRender.com.