Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

Abstract

Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either Gojo et al.Personalized Treatment of H3K27M Glioma miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

“…However, in our gliosarcoma patient with disease progression under entrectinib, no secondary NTRK mutation was detected, but molecular profiling revealed activation of alternative oncogenic pathways, including NF2 and insulin receptor ( INSR ). Whether these effects are acquired events or whether resistant tumor cells emerge from primary subclones being intrinsically resistant—as, for example, cancer stem cells—which facilitated disease progression remains to be clarified [ 38 , 39 , 40 ]. The latter could indeed be present as we have already demonstrated high intratumoral heterogeneity within other pHGG types [ 38 , 39 , 40 , 41 ].…”

Cutaneous reactions to pediatric cancer treatment part II: Targeted therapy

“…102 However, they have also been used in the treatment of pediatric patients with gliomas, ovarian cancer, and visceral leishmaniasis. [102][103][104][105] Dermatologic AEs were rarely reported in these studies; however, one small study of six patients using miransertib reported rash (67%; 4/6) and mucositis (50%; 3/6) in the cohort. and peripheral edema.…”

“…Current AKT inhibitors include miransertib, miltefosine, perifosine, and MK2206. [102][103][104][105][106][107] Similar to PIK3CA inhibitors, AKT inhibitors have been used to treat vascular anomalies and overgrowth in children. 102 However, they have also been used in the treatment of pediatric patients with gliomas, ovarian cancer, and visceral leishmaniasis.…”

Variations in attitudes towards stereotactic biopsy of adult diffuse midline glioma patients: a survey of members of the AANS/CNS Tumor Section

“…For example, Gojo et al report a small prospective study in which 10 patients' tumors underwent comprehensive molecular analysis and 90% underwent personalized treatment based on identified targetable mutations. While no overall significant survival benefit was conferred over the control cohort, only the experimental cohort had long term survivors [35]. Additionally, ONC201, a dopamine receptor D2/3 (DRD2/3) antagonist, has demonstrated clinical activity in DMG patients with the H3K27M mutation [36].…”