Rechberger, Julian S.

Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options. Among them, H3 K27-altered diffuse midline gliomas (DMG) of the brainstem stand out due to their distinct molecular features and dismal prognosis. Recent advances in molecular profiling techniques have unveiled the critical role of H3 K27 alterations, particularly a lysine-to-methionine mutation on position 27 (K27M) of the histone H3 tail, in the pathogenesis of DMG. These mutations result in epigenetic dysregulation, which leads to altered chromatin structure and gene expression patterns in DMG tumor cells, ultimately contributing to the aggressive phenotype of DMG. The exploration of targeted therapeutic avenues for DMG has gained momentum in recent years. Therapies, including epigenetic modifiers, kinase inhibitors, and immunotherapies, are under active investigation; these approaches aim to disrupt aberrant signaling cascades and overcome the various mechanisms of therapeutic resistance in DMG. Challenges, including blood–brain barrier penetration and DMG tumor heterogeneity, require innovative approaches to improve drug delivery and personalized treatment strategies. This review aims to provide a comprehensive overview of the evolving understanding of DMG, focusing on the intricate molecular mechanisms driving tumorigenesis/tumor progression and the current landscape of emerging targeted interventions.

Abstract GB13 is a novel biologic therapy in the final stages of preclinical development for the treatment of glioblastoma (GBM) and H3 K27-altered diffuse midline glioma (DMG) that has received Orphan Drug Designation by the Food and Drug Administration for treatment of malignant gliomas. GB13 targets a specific tumor-restricted receptor of interleukin 13 called interleukin 13 receptor alpha 2 (IL13Rα2). IL13Rα2 is highly expressed in malignant gliomas and, importantly, is not expressed on non-cancerous cells of the brain. GB13 consists of an engineered proprietary mutant of IL13, which binds exclusively to IL13Rα2, and is fused to a highly cytotoxic exotoxin molecule. In vitro data demonstrate that GB13 potently kills IL13Rα2+ cancer cells while sparing non-cancerous cells. These characteristics make GB13 an attractive agent for safe and efficacious targeting of tumor cells expressing IL13Rα2 in upcoming clinical trials. In the current studies, we employed patient-derived GBM and DMG cell and animal models to provide key conclusions that support GB13 as an effective treatment option for gliomas in the clinic. First, we demonstrated that single acute infusions of GB13 by enhanced delivery (CED) is effective at decreasing orthotopic tumor volumes and increasing animal survival and that a long-term infusion can more significantly extend animal survival. Second, we determined that IL13Rα2 is requisite for GB13 activity as tumors that do not express the receptor are insensitive to the cytotoxic effects of GB13, demonstrating a precise and clear biomarker for clinical trial patient selection. Finally, we determined that GB13 works in concert with clinical standard-of-care radiation therapy to increase cell death, compared to radiation alone. Based on this work, we and our clinical collaborators are confident that the current work confirms GB13 has many important characteristics as an exciting therapy, which continues development towards a Phase I clinical trial for both GBM and pediatric DMG.

Abstract H3 K27-altered diffuse midline gliomas (DMG) are uniformly lethal tumors for which no therapy has been found to be effective. The blood-brain barrier (BBB) restricts uptake and accumulation of systemically administered drugs in the brain. Convection-enhanced delivery (CED) circumvents the BBB by directly infusing therapeutics into the tumor, facilitating homogenous distribution of drugs at high local concentrations with minimal systemic toxicity. However, most drugs given by CED are rapidly cleared from the brain, severely limiting its therapeutic potential. Here, we determine the impact of drug characteristics rather than mechanism of action on compatibility with CED. Various medicinal chemistry prediction models were interrogated to define drug categories predicated on inherent physicochemical properties of the drugs. A panel of FDA-approved drugs with biologically validated activity in DMG were selected for each group: panobinostat/ponatinib, everolimus/topotecan, tolnaftate/tretinoin, and carmofur/eltrombopag. In vivo pharmacokinetic studies of these drugs delivered by CED into the pons of tumor-naïve mice showed that drugs expected to be less likely to undergo active efflux persisted at the site of infusion over prolonged periods of time. Conversely, efflux transporter (ET) substrate drugs were quickly excreted from the brain and readily detectable in the plasma following CED. Based on the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were much higher for ET substrate drugs compared with ET non-substrates, resulting in a significant increase in the residence time (the time spent by drugs in the brain) in the absence of ET-mediated clearance. These properties were further validated in efficacy studies in DMG animal models. The proclivity of many drugs to be rapidly effluxed from the brain after CED generates a vulnerability that can be exploited for the development of novel therapeutic regimens, such as with pharmacokinetics-informed drug selection or concomitant dosing of ET-inhibiting drugs.

OBJECTIVE Inferior petrosal sinus (IPS) sampling (IPSS) is a diagnostic procedure used to guide diagnostic localization of imaging-negative adrenocorticotropic hormone (ACTH)–secreting pituitary microadenomas. However, the efficacy of IPSS has been suboptimal at accurately lateralizing the adenoma, reducing surgical cure rates and leading to unintended pituitary dysfunction due to the added exploration. One rationale for the occasional imprecision is the existence of additional petrosal sinus collateral channels that connect the IPS bilaterally, which may lead to false localization results during sampling. The aim of this study was to explore a potential connection between normal anatomical variation in the angioarchitecture of the IPSs and the ACTH results obtained in subsequent IPSS tests. METHODS A retrospective review was performed on all cases between 1998 and 2013 involving patients at a single institution who underwent IPSS for radiographically equivocal pituitary microadenomas. Cases were reviewed for tumor laterality noted on either operative or pathology reports, as well as the presence of angiographic evidence of cross-filling between the sinuses. In addition, ACTH levels from the right and left IPSs were documented at baseline and at 2, 5, and 10 minutes after corticotropin-releasing hormone (CRH) administration. A ratio of the change in ACTH levels measured at the time of maximal response (10 minutes) versus the levels measured at the initial response (2 minutes) was computed for each patient and compared between patients by their angiographic cross-filling status. RESULTS There were 41 patients with a histopathologically confirmed right- or left-sided ACTH-secreting pituitary microadenoma who underwent preoperative IPSS. Among these patients, 28 (68%) showed angiographic evidence of cross-filling between the IPSs, and 13 showed no cross-filling. On average, ACTH levels increased by a factor of 3.91 ± 0.77 in the contralateral IPS in patients with angiographic cross-filling, compared with a factor increase of only 1.80 ± 0.27 in patients without cross-filling (p = 0.014). In comparison, ACTH levels increased by a factor of 2.01 ± 0.57 in the ipsilateral IPS in patients with cross-filling, and by 8.78 ± 7.30 in those without cross-filling (p = 0.373). CONCLUSIONS The presence of angiographic cross-filling, suggestive of a greater degree of vascular channel networking between the right and left IPS, is a significant factor influencing the measured rates of change of ACTH in IPSS and may impact the specificity of this test to accurately determine microadenoma laterality in the preoperative setting.

Medulloblastoma is the most common malignant brain tumor in children. Over the last few decades, significant progress has been made in revealing the key molecular underpinnings of this disease, leading to the identification of distinct molecular subgroups with different clinical outcomes. In this review, we provide an update on the molecular landscape of medulloblastoma and treatment strategies. We discuss the four main molecular subgroups (WNT-activated, SHH-activated, and non-WNT/non-SHH groups 3 and 4), highlighting the key genetic alterations and signaling pathways associated with each entity. Furthermore, we explore the emerging role of epigenetic regulation in medulloblastoma and the mechanism of resistance to therapy. We also delve into the latest developments in targeted therapies and immunotherapies. Continuing collaborative efforts are needed to further unravel the complex molecular mechanisms and profile optimal treatment for this devastating disease.

H3 K27–altered diffuse midline gliomas (DMGs) are frequently biopsied to obtain tissue diagnosis, inform clinical decision-making, and determine clinical trial eligibility. Tissue yield from biopsies is typically low, leaving little material available for research. To advance understanding of disease biology and promote preclinical testing of novel therapeutics, collecting viable cellular material from treatment-naive tumors is of paramount importance. Here, the authors report the feasibility of a practicable technique for creating DMG cell lines and patient-derived xenografts (PDXs) without the need for additional biopsy specimens. Tumor cells are obtained by probe washing immediately after completion of biopsy. Wash fluid is collected, and viable cells are expanded in vitro. Cultured cells are used to establish PDX rodent models. A total of 5 patient samples were collected by this technique. Viable tumor cells were obtained from 3 of the 5 samples, and cell lines suitable for experiments were obtained within 6–8 months. Orthotopic implantation and flank engraftment was successful in 1 of the 3 established cell lines. Animals harboring intracranial tumors were euthanized due to disease burden 6–7 months after stereotactic injection. Flank tumors formed within 4–5 months and were serially passaged. Molecular and tissue analyses confirmed retention of H3 K27M expression and loss of H3 K27me3 in all cell lines and PDXs.

Inhibition of the interaction between MDM2 and p53 has emerged as a promising strategy for combating cancer, including the treatment of glioblastoma (GBM). Numerous MDM2 inhibitors have been developed and are currently undergoing rigorous testing for their potential in GBM therapy. Encouraging results from studies conducted in cell culture and animal models suggest that MDM2 inhibitors could effectively treat a specific subset of GBM patients with wild-type TP53 or functional p53. Combination therapy with clinically established treatment modalities such as radiation and chemotherapy offers the potential to achieve a more profound therapeutic response. Furthermore, an increasing array of other molecularly targeted therapies are being explored in combination with MDM2 inhibitors to increase the effects of individual treatments. While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.

Primary brain and central nervous system (CNS) tumors are a diverse group of neoplasms that occur within the brain and spinal cord. Although significant advances in our understanding of the intricate biological underpinnings of CNS neoplasm tumorigenesis and progression have been made, the translation of these discoveries into effective therapies has been stymied by the unique challenges presented by these tumors’ exquisitely sensitive location and the body’s own defense mechanisms (e.g., the brain–CSF barrier and blood–brain barrier), which normally protect the CNS from toxic insult. These barriers effectively prevent the delivery of therapeutics to the site of disease. To overcome these obstacles, new methods for therapeutic delivery are being developed, with one such approach being the utilization of nanoparticles. Here, we will cover the current state of the field with a particular focus on the challenges posed by the BBB, the different nanoparticle classes which are under development for targeted CNS tumor therapeutics delivery, and strategies which have been developed to bypass the BBB and enable effective therapeutics delivery to the site of disease.