Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies

ABSTRACTIntroduction H3 K27-altered diffuse midline glioma (DMG) is the most common malignant brainstem tumor in the pediatric population. Despite enormous preclinical and clinical efforts, the prognosis remains dismal, with fewer than 10% of patients surviving for two years after diagnosis. Fractionated radiation remains the only standard treatment options for DMG. Developing novel treatments and therapeutic delivery methods is critical to improving outcomes in this devastating disease.Areas covered This review addresses recent advances in molecularly targeted pharmacotherapy and immunotherapy in DMG. The clinical presentation, diagnostic workup, unique pathological challenges, and current clinical trials are highlighted throughout.Expert opinion Promising pharmacotherapies targeting various components of DMG pathology and the application of immunotherapies have the potential to improve patient outcomes. However, novel approaches are needed to truly revolutionize treatment for this tumor. First, combinational therapy should be employed, as DMG can develop resistance to single-agent approaches and many therapies are susceptible to rapid clearance from the brain. Second, drug-tumor residence time, i.e. the time for which a therapeutic is present at efficacious concentrations within the tumor, must be maximized to facilitate a durable treatment response. Engineering extended drug delivery methods with minimal off-tumor toxicity should be a focus of future studies.KEYWORDS: Diffuse midline gliomaH3 K27-alteredH3 K27Mdiffuse intrinsic pontine gliomahistoneblood-brain barriertargeted therapyimmunotherapyONC201convection-enhanced deliveryDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsDespite enormous effort and more than 100 clinical trials, chemotherapy has remained ineffective in diffuse midline glioma (DMG).Current therapies being tested include small molecule inhibitors of key molecular targets, adoptive cellular immunotherapies, checkpoint inhibitors, immunotoxins, and vaccine-based interventions.Although a number of therapies for DMG have been successful in preclinical in vitro and in vivo models, the diffuse nature of these tumors and the blood-brain barrier limit the efficacy of most interventions in human patients.Combinational therapies will likely be required to effectively treat DMG.Advancing therapeutic delivery methods and maximizing drug-tumor residence time represent urgent clinical needs for DMG patients.DECLARATION OF INTERESTSThe 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 DISCLOSURESPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Figure 1. Clinical and radiographic characteristics used in diagnosis of H3 K27-altered diffuse midline glioma (DMG). (a) Clinical features used to diagnose DMG include long tract signs, ataxia/dysmetria (i.e., cerebellar signs), and cranial nerve neuropathies. (b) T1- and T2-weighted images of lesions later confirmed via biopsy as DMG (red arrows indicate tumor location). Note the hyperintensity on T2- and hypointensity on T1-weighted imaging. DMG tumors typically exhibit no or limited contrast enhancement. Figure created in BioRender.Display full sizeFigure 2. Tissue-based diagnostic workflow for DMG tumors. (a) To facilitate more granular diagnosis and elucidate specific molecular alterations, DMG tumors may be biopsied. Biopsy samples undergo immunohistochemistry staining and/or next generation sequencing to obtain detailed diagnostic information. (b) Description of H3K27M images here once we get these back from neuropathology. Figure created in BioRender.Display full sizeFigure 3. (a) DMG tumors can occur in multiple locations within the central nervous system, including (in order of frequency): pons, cortex, thalamus, midline non-thalamic, cerebellum, and spinal cord. (b) Potential mechanisms for H3K27M-driven loss of H3K27 trimethylation in DMG, which is believed to be a key driver of tumor development. Specific mechanisms include: 1) H3 K27M binds to EZH2 to sequester PRC2, preventing methylation of wild-type H3 K27 histones; 2) PCR2 is sequestered via EZH2 binding to poised enhancers; 3) H3 K27M inhibits the propagation of H3 K27me2 and me3 mediated by PCR2. Figure created in BioRender.Display full sizeFigure 4. Current therapeutic options in DMG, from standard of care (fractionated radiotherapy) to therapies under active investigation (small molecule inhibitors, immunotherapies). Figure created in BioRender.Display full sizeAdditional informationFundingThis paper was not funded.