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
• diffuse intrinsic pontine glioma
• blood–brain barrier
• targeted therapeutics
• pharmacokinetics
• convection-enhanced delivery

Article highlights

1. H3K27-altered diffuse midline glioma (DMG) is a rare but deadly brain tumor predominately found in children.

2. Despite decades of research, clinicians have not yet been able to overcome the complex obstacles for successful clinical implementation of novel therapies.

3. While some therapies may be limited by intratumoral heterogeneity or lack of sufficient exposure time, the crux in almost all therapies is the blood–brain-barrier (BBB).

4. To circumvent the BBB, convection-enhanced delivery (CED) has emerged as a safe technique to deliver drugs directly into the tumor with additional optimization currently underway in preclinical and clinical studies.

5. A successful therapy for DMG tumors will likely require that we are able to get a cytotoxic drug to the tumor and keep it there for long enough to elicit its effects.

This box summarizes key points contained in the article.

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. No financial or material support was received for this research or the creation of this work.

Reviewer disclosures

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

Author contributions

Conception and design: Rechberger, Nesvick, Daniels. Drafting the article: Rechberger, Power B. Critically revising the article: Rechberger, Power B, Power E, Nesvick, Daniels. Creating the figures: Rechberger, Power E. Reviewed submitted version of manuscript: Rechberger, Nesvick, Daniels. Approved the final version of the manuscript on behalf of all authors: Rechberger. Article supervision: Daniels.

Additional information

Funding

This paper was not funded.