Phase I/II trial of vorinostat and radiation and maintenance vorinostat in children with diffuse intrinsic pontine glioma: A Children's Oncology Group report.

BACKGROUND: A phase I/II trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor, was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) through the Children's Oncology Group (COG) to: 1) determine the recommended phase II dose (RP2D) of vorinostat given concurrently with radiation therapy; 2) document the toxicities of continuing vorinostat as maintenance therapy after radiation; and 3) to determine the efficacy of this regimen by comparing the risk of progression or death with a historical model from past COG trials. METHODS: Vorinostat was given once daily, Monday through Friday, during radiation therapy (54 Gy in 30 fractions), and then continued at 230 mg/m2 daily for a maximum of twelve 28-day cycles. RESULTS: Twelve patients enrolled in the phase I study; the RP2D of vorinostat given concurrently with radiation was 230 mg/m2/day, Monday through Friday weekly. The six patients enrolled at the RP2D and an additional 64 patients enrolled in the phase II study contributed to the efficacy assessment. Although vorinostat was well-tolerated, did not interrupt radiation therapy, and was permanently discontinued in only 8.6% of patients due to toxicities, risk for EFS-event was not significantly reduced compared with the target risk derived from historical COG data (P = 0.32; 1-sided). The 1-year EFS was 5.85% (95% CI 1.89-13.1%) and 1-year OS was 39.2% (27.8-50.5%). CONCLUSIONS: Vorinostat given concurrently with radiation followed by vorinostat monotherapy was well tolerated in children with newly diagnosed DIPG but failed to improve outcome.

Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although outcomes have improved in recent decades, new treatments are still needed to improve survival and reduce treatment-related complications. The MB subtypes groups 3 and 4 represent a particular challenge due to their intragroup heterogeneity, which limits the options for "rational" targeted therapies. Here, we report a systems biology approach to drug repositioning that integrates a nonparametric, bootstrapping-based simulated annealing algorithm and a 3D drug functional network to characterize dysregulated driver signaling networks, thereby identifying potential drug candidates. From more than 1300 drug candidates studied, we identified five members of the cardiac glycoside family as potentially inhibiting the growth of groups 3 and 4 MB and subsequently confirmed this in vitro. Systemic in vivo treatment of orthotopic patient-derived xenograft (PDX) models of groups 3 and 4 MB with digoxin, a member of the cardiac glycoside family approved for the treatment of heart failure, prolonged animal survival at plasma concentrations known to be tolerated in humans. These results demonstrate the power of a systematic drug repositioning method in identifying a potential treatment for MB. Our strategy could potentially be used to accelerate the repositioning of treatments for other human cancers that lack clearly defined rational targets.

Novel somatic and germline mutations in intracranial germ cell tumours.

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

Embryonal central nervous system neoplasms arising in infants and young children: a pediatric brain tumor consortium study.

CONTEXT: Medulloblastomas (MBs) and atypical teratoid/rhabdoid tumors (AT/RTs) arising in infants and children can be difficult to distinguish; however, histologic characterization is prognostically important. OBJECTIVE: To determine histologic and phenotypic markers associated with utility with progression-free survival (PFS) and overall survival (OS) in children younger than 3 years with MBs and AT/RTs. DESIGN: We undertook a histologic and immunophenotypic study of MBs and AT/RTs arising in infants and children younger than 3 years treated in a Pediatric Brain Tumor Consortium study. The 41 girls and 55 boys ranged in age from 2 to 36 months at enrollment. These infants and children exhibited 51 MBs, 26 AT/RTs, and 24 other tumors (not further studied). Median follow-up of the patients was 17.2 months from diagnosis (range: 1.4-93 months). RESULTS: Infants and children with AT/RT exhibited a statistically significant shorter PFS and OS when compared to infants and children with MBs (both P < .001). A lack of nuclear BAF47 immunohistochemical reactivity proved reliable in identifying AT/RTs. Among MBs, our data suggest an association of nodularity and prolonged PFS and OS, which must be independently confirmed. Anaplasia correlated with OTX2 reactivity and both OTX2 and moderate to severe anaplasia correlated with PFS but not with OS. CONCLUSION: Distinguishing AT/RT from MBs is clinically important. For expert neuropathologists, the diagnoses of AT/RT and MB can be reliably made from hematoxylin-eosin stains in the vast majority of cases. However certain rare small cell variants of AT/RT can be confused with MB. We also found that immunohistochemical reactivity for BAF47 is clinically useful in distinguishing MBs from AT/RTs and for identifying certain small cell AT/RTs. Among MBs, nodularity may be an important prognostic factor for improved PFS and OS in infants and children.