Highlights from the Literature

The standard management of patients with glioblastoma currently involves a combination of surgical resection with adjuvant concurrent chemoradiation therapy. Elderly patients with glioblastoma are challenging to manage due to their frequent complicating comorbidities and due to the toxic effects of available treatment options. Moreover, these patients have largely been under-represented in most randomized trials, and therefore evidence guiding optimal management is largely lacking. In this manuscript, Perry and his colleagues report on an international, randomized, multicenter trial evaluating the efficacy of a short-course chemoradiation treatment regimen for elderly patients with glioblastoma. In this trial, all patients were more than 65 years old with newly diagnosed glioblastoma confirmed by histology and Eastern Cooperative Oncology Group (ECOG) performance status 0–2. Eligible patients were deemed unsuitable to receive adjuvant conventional chemoradiation therapy (60 Gy in 30 fractions over 6 weeks with temozolomide) by their treating physicians and were randomized to receive either abbreviated chemoradiation (40 Gy in 15 fractions over 3 weeks with temozolomide) or abbreviated radiotherapy alone less than 28 days after initial surgery. There were 562 patients who underwent randomization with 281 patients assigned to each arm of the trial. The median age of patients enrolled was 73 years (range from 65–90 years) and the median follow-up was 17 months. The majority of patients were enrolled from centers in Europe and Canada. Approximately half of the patients had MGMT methylation. In the primary endpoint of the study, overall survival was improved with abbreviated chemoradiation compared with radiation alone (median 9.3 months versus 7.6 months, hazard ratio, 0.67; 95% CI 0.56–0.80; P < 0.001). Chemoradiation was also associated with longer progression-free survival compared with radiation alone (5.3 months versus 3.9 months, HR, 0.50; 95% CI 0.41–0.60; P < 0.001). In subset analyses, chemoradiation was beneficial compared with radiation alone in MGMT-methylated cases. Interestingly, there was also a tendency for improved overall survival in MGMT-unmethylated patients that did not reach statistical significance (P = 0.055, median 10.0 months versus 7.9 months). Combined chemoradiation did not change the rates of serious adverse events leading to death, and there was no difference in quality of life scores between the two groups. This trial is the first large randomized trial to clearly show the effectiveness of a short-course chemoradiation regimen compared with radiation therapy alone for elderly patients with glioblastoma. In oncology, there are continuing efforts to simplify treatment strategies in elderly patients, as an abbreviated chemoradiation regimen allows for improved adherence to the treatment protocol and spares patients the deleterious effects of high-dose radiation. In fact, the NOA-88 trial had demonstrated that temozolomide therapy alone is non-inferior to radiotherapy alone in elderly patients with malignant gliomas. Therefore, it is possible that the survival benefit conferred in this trial is due mainly to temozolomide use, suggesting that elderly patients may be spared radiotherapy in its entirety. This possibility could be explored in future trials; however, at present, standard treatment for elderly patients with glioblastoma continues to include combination chemoradiation therapy. Although this study lends evidence for the effectiveness of an abbreviated treatment course in elderly patients with glioblastoma, there have not been any direct head-to-head comparisons of abbreviated versus conventional chemoradiation treatment strategies. Interestingly, younger patients aged 65–70 years derived less benefit from chemoradiation than patients aged 71–75 years and older than 76 years, which perhaps runs counter to the notion the older age is uniformly associated with poorer outcome in glioblastoma. The importance of this study lies in the examination of the combination of temozolomide and radiation therapy in older adults, who account for half of all patients currently and, with the ageing of our population, may represent a larger proportion of overall patients with glioblastoma. Cancer stem cells (CSC) are a self-renewing, pluripotent, and tumorigenic population that drive tumor cell growth and resistance to therapy in many cancers, including glioblastoma. Toll-like receptors (TLR) play key roles in the innate immune system, where they activate inflammatory response pathways and recruit immune cells. TLRs can act as pro- or anti-tumorigenic in different cancers. To understand how CSCs survive hostile environments in the setting of innate immune suppression, a recent study by Alvarado et al. investigated the role of TLRs in glioblastoma CSCs (GSCs). The study found that TLR4 is immune suppressive in glioblastoma and that GSCs evade innate immune suppression by downregulation of TLR4 expression. The authors first investigated the effects of several TLR ligands on the proliferation of GSCs and non-GSCs. They found that only the TLR4 ligands lipopolysaccharide (LPS) and high mobility group box 1(HMGB1) had differential effects on the two populations, where they inhibited non-GSCs but not GSCs. They showed that TLR4 is expressed at a lower level in GSCs than in non-GSCs, potentially explaining their differential responsiveness to TLR4 activation. TLR4 expression also negatively correlated with GSC markers and with self-renewal. To determine the effects of TLR4 in GSCs, the authors overexpressed TLR4 and found that this led to a decrease in GSC stemness, expression of self-renewal genes, and cell proliferation as well as to the inhibition of in vivo xenograft growth. To uncover the mechanism through which TLR4 inhibits GSC functions, the authors hypothesized that TLR4 might regulate the transcription of GSC self-renewal genes (SOX2, NANOG, OCT4). Consequently, they used a combination of self-renewal gene promoter analysis and mRNA differential expression analysis and identified retinoblastoma binding protein 5 (RBBP5) as a candidate mediator of the effects of TLR4 in GSCs. They experimentally confirmed the involvement of RBBP5 by showing that TLR4 overexpression leads to inhibition of RBBP5 expression and activity in GSCs. They subsequently demonstrated that RBBP5 regulates the GSC phenotype by showing that RBBP5 silencing decreases the expression of self-renewal genes, self-renewal, and tumor initiation capacity. Finally, the authors used Ingenuity Pathway Analysis with TLR4, SOX2, and RBPP5 as nodes to identify and then experimentally verify tank binding kinase 1 (TBK1) as a mediator of the effects of TLR4 on RBPP1 and GSC phenotype. The study showed that TLR4 downregulation allows GSCs to evade innate immune suppression and identified TBK1 upregulation and RBPP5 inhibition as events mediating the effects of TLR4 on GSCs. The findings of this study uncover a mechanism through which GSCs persist in hostile environments because of an inability to respond to inflammatory signals. The findings also provide a potential opportunity to target the TLR4/TBK1/RBBP5 axis for glioblastoma therapy. Central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) is a rare, clinically aggressive tumor, most commonly affecting children under 3 years of age and belonging to the larger family of rhabdoid tumors. AT/RT and other rhabdoid tumors have been linked to somatic and germline mutations of SMARCB1, a known tumor suppressor gene and core component of the SWI/SNF chromatin-remodeling complex. The quiet genomes of these tumors seem a stark contrast to their highly aggressive nature, suggesting an epigenetic mechanism may underlie tumor formation. Currently, there is no standard treatment for children with this disease. For children with CNS rhabdoid tumors, in particular, known factors associated with poor outcome include germline mutation, age younger than 2 years, metastases at diagnosis, and subtotal resection. Despite the fact that the majority of published information on outcomes for these patients draws on small retrospective series, one common theme persists—patients affected by this disease are in need of novel therapies. The recent letter in Nature Genetics by Wang and colleagues may begin to offer insight into future potential therapeutic targets. Analysis of brain-derived rhabdoid tumors showed enrichment for active enhancers near neurogenesis-related genes; tumor-specific super-enhancers, which possess elevated levels of acetylated histone H3 at lysine 27, highlight key regulators of neural development like SOX2, which may be essential for tumor cell survival. Their observations further suggest that SMARCB1 functions differently with regard to differentiation-related regular enhancers and super-enhancers by activating the former and leaving the latter generally unaffected. Specifically, loss of SMARCB1 leads to decreased levels of the SWI/SNF complex, thereby reducing enhancer targeting and impairing their function. The small amount of residual SWI/SNF complex then preferentially binds to the super-enhancers helping to maintain aberrant cell identity. The authors go on to hypothesize that for certain progenitor cell types, reduced enhancer function in the setting of preserved super-enhancer function may actually drive tumor formation by keeping cells in a poorly differentiated, yet highly proliferative state. How this new information will translate to identifying new therapies for these patients remains to be seen, but it provides a stepping-stone for oncologists and researchers to begin to think about better agents and methods to treat these tumors. IDH mutations are common in lower-grade gliomas and secondary glioblastomas, and mutant IDH protein converts α-ketoglutarate (αKG) to the R enantiomer of 2-hydroxyglutarate [(R)-2HG], which is thought to inhibit the activity of αKG-dependent dioxygenases. 2HG is postulated to function as an oncometabolite that alters multiple cellular processes, including cell proliferation and epigenetic programming. Overall, IDH-mutant gliomas appear to confer an improved prognosis over grade-matched IDH-wild type gliomas, perhaps as a function of response to radiation and chemotherapy.1–4 In an elegant manuscript, Sulkowski et al examined the mechanistic influence of IDH1/2 mutations on the DNA damage repair process and proposed therapeutic implications for their findings.5 The authors utilized cell line pairs, expressing mutant or wild-type IDH proteins, and examined DNA double-strand break (DSB) repair. IDH-mutant expressing cells consistently showed a defect in homologous recombination (HR) that contributed to sensitization of the cells to poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) inhibition. For example, synthetic lethality was observed in several IDH-mutant cell lines with the PARP inhibitor BMN-673 at a level similar to what was observed in BRCA-2 deficient cells, prompting the suggestion that IDH mutations induce a “BRCAness” phenotype that features chemo- and radiation sensitivity and PARP inhibitor synthetic lethality, but independent of BRCA1/2 mutations. In addition to genetic engineering, double-stranded break (DSB) repair defects were also observed upon exposure of immortalized human astrocytes to 2HG enantiomers. The opposite of this effect was observed when cells were exposed to exogenous αKG, which led to a decrease in DNA DSBs in IDH1 mutant HeLa cells. On the other hand, neutralizing mutant IDH1 by either siRNA or small molecule inhibitors rescued the observed defect in HR and sensitivity to PARP inhibition, confirming that the defects in DSB repair are likely due to functional inhibition of αKG-dependent dioxygenases. A focused siRNA screen targeting all major αKG-dependent dioxygenases led to the identification of KDM4A and KDM4B. Forced expression of KDM4A or KDM4B was able to rescue the DNA DSB repair defect in mutant-IDH1-expressing cells but had no effect on IDH1 wild-type cells. With these data, the authors uncover an unexpected therapeutic vulnerability intrinsic to IDH1/2 mutations in glioma, and suggest that the presence of this mutation can be harnessed for therapeutic exploitation. At first glance, this concept may run counter to a current trend of specific inhibition of mutant IDH activity in glioma. Findings in this manuscript may spur additional pre-clinical work into the effectiveness of PARP inhibitors in IDH1/2 mutant gliomas. Although translational utility of these findings must be further validated using in vivo xenograft models or patients treated with PARP inhibitors, the new concept presented here warrants additional investigation. Intracranial germ cell tumors (iGCT) are among the most common brain tumors in children below the age of 14 in Japan. In order to molecularly define the distinct histologic subtypes Fukushima et al1 subjected 61 GCTs to genome-wide DNA methylation analysis using the Illumina Human Methylation450K platform. Using the most variable probes, three main methylation subgroups emerged: the global low methylation subgroup (GLM) that comprised only pure germinomas (16/25), the partial low methylation subgroup consisting of pure germinomas and some non-germinoma germ cell tumors (NGGCT), and the high methylation (HM) subgroup was characterized by NGGCT (31/36) and comprised the normal tissues including ovary and testes but only 3/25 pure germinomas. The most striking observation was the low methylation beta-values in the pure germinomas. This was further underlined when the authors used a random set of methylation probes and compared it to other tumor types or normal tissues. In order to reveal the biological underpinnings, the methylation profiles were compared in a sex-dependent manner to DNA methylation patterns specific to distinct developmental stages of primordial germ cells (PGCs) in the mouse.2 Using the set of over 9000 matched genes, pure germinomas clustered with PGCs, whereas NGGCT and normal tissues clustered separately. PGCs characteristically show progressive loss of methylation marks of imprinted genes, X-linked genes (females), and some germ cell-specific genes as a consequence of methylation erasure followed by sex-dependent “re-establishment” during development. From the differential methylation patterns observed for the distinct types of genes at specific developmental stages, the pure germinomas resembled most PGCs in the migration phase (E10.5), uncovering them as a potential cell of origin. Interestingly, long interspersed nuclear element 1 (LINE1) displayed pronounced hypomethylation in pure germ cell tumors, which is in contrast to PGCs. The authors associated the extraordinary LINE1 hypomethylation observed in pure germinomas with high genetic instability in the tumors that may represent an underlying cause of their particular malignancy. Macro-dissection of histologically mixed tumors revealed distinct DNA methylation patterns but identical mutations in MAPK or PI3K pathways. This suggests a common origin and implies that the mutations precede the epigenetic deregulation. Taken together, this is an elegant study providing a model for the origins of iGCT. The model was built by integrating genetic and epigenetic data from tumors with data characterizing dynamic epigenetic changes during the development of PGCs in the mouse. These insights will now allow the development of respective in vitro and in vivo models for further investigations. Active site mutations in the isocitrate dehydrogenase enzymes IDH1 and IDH2 essentially define the pathogenesis of lower-grade diffuse gliomas. Nevertheless, the precise oncogenic driver events induced by IDH mutation remain unclear. A large subset of IDH-mutant gliomas—primarily those also featuring 1p/19q codeletion—harbor activating mutations in the TERT promoter, leading to increased TERT transcription and telomerase activity. Interestingly, almost all remaining IDH-mutant gliomas contain mutations in the ATRX gene that promote alternative lengthening of telomeres by way of endogenous homologous recombination mechanisms. In this way, genetic evidence strongly suggests that pathological telomere maintenance is absolutely required for IDH-mutant gliomagenesis. In a recent Cancer Research paper, Ohba et al. investigated whether and how IDH mutation engages and augments telomere maintenance. Using pRB/p53-deficient normal human astrocytes (NHAs) as their primary model system, they demonstrated that the additional expression of TERT was required for sustained immortalized growth. In the absence of TERT, telomere-induced crisis abrogated cell growth. However, in this setting they found that expression of mutant, but not wild-type, IDH1 allowed escape from telomere-induced crisis, immortalized growth, colony formation in soft agar, and even orthotopic xenografts in some cases. Importantly, the established oncogenic driver HRasV12 was unable to rescue NHAs from telomere-induced crisis, emphasizing the specificity of this effect to mutant IDH1. The authors went on to show that the effects of mutant IDH1 on cellular immortalization were not due to either histone or DNA methylation, the extents of which did not change between pre- and post-crisis NHAs. Moreover, whereas genomic alterations were acquired during the transition, mutations in ATRX and/or TERT were not identified. Instead, IDH mutation resulted in endogenous activation of TERT expression by way of focused increases in H3K4 trimethylation at the gene’s promoter region along with binding of the transcription factor Max. The significance of this paper lies in its systematic recapitulation of oncogenic driver events for IDH-mutant gliomas in disease-relevant cellular and molecular contexts. Moreover, Ohba et al confirm that the resolution of telomeric dysfunction is, in fact, essential in the IDH-mutant context, and also occurs readily. Finally, this work provides a model system for the small but significant number of IDH-mutant tumors that lack both ATRX and TERT mutations.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.