Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit

Pediatric high-grade gliomas (pHGG) are a molecularly diverse group of malignancies, each incredibly aggressive and in dire need of treatment advancements. Genomic analysis has revolutionized our understanding of these tumors, identifying biologically relevant subgroups with differing canonical mutational profiles that vary based on tumor location and age. In particular, the discovery of recurrent histone H3 mutations (H3K27M in diffuse midline glioma, H3G34R/V in hemispheric pediatric high-grade gliomas) as unique “oncohistone” drivers revealed epigenetic dysregulation as a hallmark of pediatric high-grade gliomas oncogenesis. While reversing this signature through epigenetic programming has proven effective in several pre-clinical survival models, early results from pediatric high-grade gliomas clinical trials suggest that epigenetic modifier monotherapy will likely not provide long-term disease control. In this review we summarize the genetic, epigenetic, and cellular heterogeneity of pediatric high-grade gliomas, and highlight potential paths forward for epigenetic programming in this devastating disease

PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS

Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation

The effect of ω-fatty acids on mrna expression level of PPARγ in patients with gastric adenocarcinoma

Background: The antineoplastic role of peroxisome proliferator-activated receptor gamma (PPARγ) ligandshas previously been demonstrated in several gastric cancer cell lines. Activation of PPARγ by polyunsaturated fatty acids (PUFAs) inhibits growth and proliferationof tumor cells. In this double-blind clinical study, we evaluate the effect of PUFAs on PPARγ mRNA expression in patients with gastric adenocarcinoma. Materials and Methods: A total of 34 chemotherapy-naive patients diagnosed with gastric adenocarcinoma were enrolled in the present study. According to treatment strategies, all subjects were divided into two groups, the first group (17 individuals) received cisplatin without supplements and the second group (17 individuals) received cisplatin plus orally administered PUFAs supplements for 3 weeks. The gastric biopsy samples were obtained from all participants before and after treatment, and PPARγ mRNA expression levels were evaluated by quantitative real-time polymerase chain reaction using validated reference genes. Results: Our findings revealed that PPARγ mRNA expression is significantly upregulated in group II afterreceiving cisplatin plus orally administered PUFAs supplements for three weeks (p < 0.0001), whereas PPARγ mRNA expression did not show significant alteration in group I after receiving cisplatin alone. Conclusion: The results of the study evidence that PPARγ may act as a potential target for the therapy of human gastric adenocarcinoma

Neuro-Oncology Practice Clinical Debate: targeted therapy vs conventional chemotherapy in pediatric low-grade glioma.

The treatment of children with low-grade glioma has evolved over the last several decades, beginning initially with focal radiotherapy, which has now been largely replaced by systemic treatment with conventional chemotherapy agents or more recently molecularly targeted therapeutics. A consensus standard of care is not well defined, leaving clinicians and parents to choose from an increasing number of options, often without complete information concerning the associated risks and benefits. Issues critical to this topic include timing of interventions (when to treat), preservation of neurological function (goals of treatment), choice of initial therapy strategy (conventional cytotoxic chemotherapy vs molecularly targeted therapy), duration of treatment (how long, and what clinical or imaging endpoints to consider), and perhaps most important, risk reduction relative to anticipated benefit. The groups from the University of California, San Francisco and Dana Farber Cancer Institute, moderated by Michael Prados, herein debate the merits of cytotoxic chemotherapy and targeted therapeutics as initial treatment strategies in pediatric low-grade glioma, a topic discussed daily in Tumor Boards across the United States and abroad. Prospective, randomized, phase 3 trials comparing the 2 strategies, conducted within homogenous disease settings, with consistently evaluated functional and imaging endpoints, are not available to guide the risks/benefit discussion. As is often the case in rare biologically diverse diseases, in a vulnerable population, therapy decisions are frequently based on incomplete data, physician experience, bias to some degree, and patient/family preference