Year: 2018
Type: article
Abstract: Posterior fossa ependymoma-B (PFB) has been considered for de-escalation of therapy due to the excellent overall survival following gross total resection1: thus, this group could potentially be spared the long-term side effects of radiation and/or chemotherapy.2 However, to move forward, unraveling the heterogeneity within PFB would be important. To discern the molecular heterogeneity within PFB, Cavalli and co-workers3 performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlations across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors (PFB1-5) with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 were discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5. Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes, and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike PFA ependymomas, 1q gain was not a robust marker of poor progression-free survival, whereas chromosome 13q loss could represent a novel marker for risk stratification. Even when accounting for the molecular heterogeneity, extent of resection remained the strongest predictor of poor outcome. This cohort of PFB ependymomas is the largest to be analyzed thus far and the first that has shown molecular heterogeneity. The observation that late relapse is common in PFB tumors highlights that long-term follow-up is required for any eventual trial of de-escalation of therapy. The systemic treatment of brain metastases (BM) continues to evolve as illustrated by two recent reports that both concern patients with non-small-cell lung cancer (NSCLC) and either EGFR T790M mutation-positive or ALK mutation-positive disease metastatic to the central nervous system (CNS).1,2 In both studies, patients were treated with a next-generation tyrosine kinase inhibitor (TKI) according to standard TKI-based therapy: osimertinib in the randomized phase III AURA3 trial or brigatinib in the collated phase I/II and randomized phase II ALTA trials. Both TKI trials were retrospective analyses using central radiology review of patients with NSCLC, BM, and sensitizing mutations who had been treated previously with and progressed on first-generation TKIs. Neither study mandated patients without baseline BM, the majority of patients in both analyses, or CNS imaging and consequently was unable to determine whether either TKI prevented or delayed the development of brain metastases. The brigatinib studies excluded patients with symptomatic BM regardless of prior CNS-directed therapy. Overall, approximately 60% of the 203 patients analyzed had been treated with radiotherapy, most with whole-brain radiotherapy. The separation of BM patients into stable treated, treated progressive, and untreated cohorts, however, was unclear. Further, and common to most trials, there was no definition of what constituted progressive disease in brain aside from an independent investigator assessment. Measurable BM were defined as ≥10 mm in maximum diameter without regards to prior therapy or disease response. Response assessments in brain used RECIST rather than RANO-BM. Nonetheless, the overall response rate was >50% in brain with a duration of response of approximately 10 months. In the osimertinib trial, any patient with asymptomatic stable BM entered the study (n = 116), of which nearly one third had had prior radiotherapy. Measurable lesions were defined as ≥10 mm in maximum diameter without regards to prior therapy. Overall response rate in brain was 70% in patients with measurable disease with a median duration of response of 9 months. These studies demonstrate compelling activity of these novel TKIs in patients with NSCLC, BM, and sensitizing mutations in either EGFR or ALK, further increasing systemic therapy options for patients with CNS metastases. BRAF is a prominent oncogenic driver in a number of cancers, and this includes pediatric brain tumors such as pilocytic astrocytomas, gangliogliomas, and pleomorphic xanthoastrocytomas. The V600E mutation is a common activator of BRAF in these tumors, but other BRAF-activating genetic lesions may be found instead. Inhibitors of BRAF alone or in combination with inhibitors of its downstream target MEK were first proven to be effective in V600E-positive melanoma and are FDA approved, but they have also begun to show promising signs of activity in brain tumors with this mutation.1 However, a new report from Wang et al. raises the concern that a secondary, dimerizing BRAF mutation can trigger resistance to this strategy in a V600E-positive pediatric brain tumor.2 The authors present the case of a 15-year-old patient initially presenting with a low-grade glioma and later progressing to an anaplastic ganglioglioma positive for the BRAF V600E mutation. After progression following surgery, radiation, and multiple chemotherapies, treatment with the ATP-competitive RAF inhibitor dabrafenib yielded a complete radiographic response lasting 40 weeks. The subsequent recurrent tumor was resected and characterized with whole-exome and RNA sequencing, which indicated a BRAF L514V mutation not present in the tumor prior to dabrafenib treatment. This mutation was further studied in vitro in a number of cellular contexts, including BRAF V600E-positive brain tumor and melanoma lines. BRAF L514V could drive BRAF signaling through MEK and ERK, and the addition of a BRAF L514V mutation in cis to V600E induced resistance to dabrafenib. Furthermore, this resistance was found to arise through dimerization of RAF, in contrast to the monomeric activity of BRAF V600E. MEK inhibitors had modest activity against melanoma cells with BRAF V600E/L514V, whereas experimental RAF dimer inhibitors or an ERK inhibitor were active against both monomeric BRAFV600E and dimeric V600E/L514V. This is the first demonstration of a secondary resistance mutation in BRAF, although similar mutations have been induced by drug inhibitors of receptor tyrosine kinase (RTK) drivers in other cancers. While this finding is worrisome as a potential limitation of RAF inhibitors now in the clinic for V600E-driven tumors, it remains to be seen whether this is a widespread phenomenon. Furthermore, the suggested efficacy of RAF dimer inhibitors and ERK inhibitors now in the pipeline provides further hope for limiting the impact of this resistance mechanism. Immune checkpoint inhibitors have had a significant impact on some cancers such as melanoma and non-small-cell lung cancer in prolonging survival rates. However, immunotherapy-based clinical trials have largely been ineffective in impacting outcome of glioblastoma (GBM) patients. This has been, at least in part, due to the lack of tumor-infiltrating lymphocytes (TILs) in the brain tumor microenvironment, and it is unclear if this is caused by the inability of T cells to breach the blood-brain barrier or by peripheral T cell exhaustion. A recent study by Chongsathidkiet et al now uncovers a novel mechanism that explains reduced TILs in GBM.1 Building on previous reports describing systemic T cell lymphopenia (low levels of lymphocytes) in GBM,2 the authors examined a cohort of treatment-naïve GBM patients for blood counts. They observed reduced CD4 and CD8 T cell counts in these patients, and in about 15% of the cases, the counts were as low as those seen in patients affected by acquired immunodeficiency syndrome. This was accompanied by a reduced spleen volume in GBM patients compared with control subjects. To examine if the diminished T cell counts and splenic contraction could be induced by brain tumors in experimental models, the authors implanted murine glioma cells via intracranial injections. In these mice, they observed a specific reduction of T cell counts but no changes in natural killer cells or myeloid cells. Interestingly, a re-distribution of T cells to the bone marrow compared to circulation in both patients and in mice bearing xenografts was observed. To examine if the location or the type of the tumor influenced T cell accumulation in the bone marrow, the authors implanted non-central nervous system tumors intracranially or subcutaneously. Interestingly, regardless of the tumor type, only intracranial injections caused T cell re-distribution. The authors went on to show that the sphingosine-1-phosphate receptor 1 (S1P1), a G protein-coupled receptor that binds the second messenger sphingosine-1-phosphate (S1P), plays a role in the exit of T cells from the bone marrow. Intracranial tumors induced a loss of S1P on T cells, which mediated their sequestration in the bone marrow. Using a S1P1 knock-in approach, the authors further show that re-expressing S1P1 in T cells abrogated T cell sequestration in mouse models. Furthermore, tumors from the S1P1 knock-in mice had higher CD3+ TILs. Finally, although increased TILs were seen in these mice, no improvement in survival was seen compared with control groups. However, combined treatment with a T cell-activating therapy (4-1BB agonist) caused significant increases in survival. This study is an important milestone in elucidating T cell dysfunction in GBM. Future studies focusing on pharmacological agents that can prevent brain tumor-induced S1P internalization must be prioritized. While it is evident from several publications that the true number and nature of molecular subgroups of medulloblastoma may not be entirely well defined, the majority if not all will agree medulloblastoma comprises more than a single disease entity. Molecular subgroups identified using mRNA expression and DNA methylation array data are designated standards for the WHO classification of medulloblastoma, yet we still struggle clinically with treatment for particular subgroups. In our continued drive to identify less toxic, more effective therapies, Archer et al. profiled the proteomes of a number of medulloblastoma samples.1 This departure from our tendency to focus on genomics offers the opportunity to evaluate the functional proteins in cells and actual conditions under which they work. The vast majority of pediatric tumors possess quiet genomes compared to adult cancers, which generally exhibit higher mutational burdens. Whether proteomics can identify therapeutic targets in tumors with low mutational rates, however, as in the case of pediatric medulloblastoma, is an unanswered question that Archer and colleagues set out to address. Interestingly, the authors are able to show that proteomic and phosphor-proteomic datasets identify similar subgroup designations for well-established subgroups like WNT and SHH. This finding contrasts with studies in some adult solid tumors in which molecular subgroups are not preserved across data subtypes. The authors hypothesize this may in fact be due to distinct developmental states with regard to medulloblastoma’s cell of origin and certain subgroup-specific genetic driver events. Their data does suggest a different distinction among the two previously reported SHH subgroups that does not involve age but rather post-transcriptional changes. Proteins higher in SHHa included those associated with the MYC pathway, chromatin remodeling, and DNA repair. SHHb tumors were enriched for pathways associated with group 4 medulloblastoma, including glutamate signaling, also known to be associated with gliomas. The authors identified CD47 as a potential candidate target; studies testing anti-CD47 antibodies are already underway for other subgroups of medulloblastoma. PRKDC, which functions in concert with MYC in the presence of DNA damage and whose inhibition may serve as a radiation sensitizer for MYC-activated group 3 medulloblastoma, provides another potential target. This study highlights a number of molecular mechanisms not evident through analyses of the genome, epigenome, or transciptiome and hence the importance of understanding the functional state of cancer cells through protein expression and post-translational modifications, fields yet to be more actively mined in the search for better treatments.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4245556895