Teasing Apart the Molecular Subtypes of Glioblastoma Reveals a Group of Patients With Predictive Markers of Treatment Response Despite the wealth of genomic information revealed by the molecular profiling of glioblastoma (GBM) subtypes, little of that information has translated into prognostic and predictive markers of treatment response, with the notable exception of the IDH1 mutation.1 Using a different approach that did not focus a priori on GBM subtypes, Cosset and colleagues recently revisited the correlation between GBM prognosis and expression of integrin beta subunits,2 which have long been known as markers of poor survival but have shown disappointing results as molecular targets in clinical trials.3 The investigators discovered a subset of gliomas characterized by poor survival and high co-expression of integrin β3 (ITGB3) and the glucose transporter Glut3. Analysis of conventional GBM cell lines revealed that ITGB3 can control Glut3 expression, making cells with high co-expression of both genes dependent on Glut3 activity for survival. However, when the experiments were repeated in more heterogeneous cultures of GBM stem cells (GSCs), neither ITGB3, Glut3, nor their co-expression were sufficient to explain the metabolic addiction to glucose and sensitivity to ITGB3 inhibitors (cilengitide). Instead, the expression of ITGB3 and Glut3 became relevant when combined with the molecular GBM subtype: GSCs with high expression of ITGB3 and Glut3 only exhibited the glucose-addicted, cilengitide-sensitive phenotype when they expressed genes from the proneural or classical subtypes, whereas this vulnerability was absent in mesenchymal GSCs independent of their ITGB3/Glut3 expression. Moreover, the proneural/classical signature found in ITG3-dependent, Glut3-dependent GSCs was not a bystander feature but was actually necessary to make those cells sensitive to low glucose or integrin inhibitors. While some important questions remain (for example: what mechanisms unique to proneural and classical GBMs can explain the sensitivity of ITG3high/Glut3high GBMs to treatments), the results highlight two important conclusions: First, within the molecular subtypes of GBM it is possible to identify groups of individuals with vulnerable gene dependencies. Second, and more important, the molecular markers that define those groups (e.g., co-expression of ITGB3, Glut3, and a proneural/classical signature) can predict response to treatments targeting their molecular vulnerability. This study underscores the importance of finding predictive markers that can be used to select prospective “responder” patients, advancing the personalized treatment of GBMs. References 1. Ceccarelli M, Barthel FP, Malta TMet al. ; TCGA Research Network. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell . 2016; 164( 3): 550– 563. Google Scholar CrossRef Search ADS PubMed 2. Cosset E, Ilmjarv S, Dutoit Vet al. Glut3 addiction is a druggable vulnerability for a molecularly defined subpopulation of glioblastoma. Cancer Cell . 2017; 32( 6): 856– 868.e855. Google Scholar CrossRef Search ADS PubMed 3. Nabors LB, Fink KL, Mikkelsen Tet al. Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol . 2015; 17( 5): 708– 717. Google Scholar CrossRef Search ADS PubMed Toward the Complete Control of Brain Metastases Using Surveillance Screening and Stereotactic Radiosurgery With the development of improved systemic therapies for cancer that target predominantly extracranial disease, the incidence of brain metastases is rising. Although brain metastases can cause neurological morbidity, particularly when larger in size or associated with brain edema, subcentimeter lesions are frequently asymptomatic. Stereotactic radiosurgery (SRS) is an effective treatment modality for brain metastases, achieving high local control (LC) rates and typically avoiding neurocognitive toxicities associated with whole-brain radiotherapy (WBRT). Reported 1-year LC rates vary from 71% to greater than 90% based on a recent systematic review.1 Tumor size is an important predictor of SRS response, with larger volumes predicting local tumor failure.2 In a recent paper in the Journal of Neurosurgery, Wolf and co-workers3 reported a retrospective study whose purpose was to determine if there is a threshold tumor size below which LC rates approach 100% and to relate these findings to the use of routine surveillance brain imaging. From a prospective registry, 200 patients with 1237 brain metastases were identified who underwent SRS between December 2012 and May 2015 at a single institution in New York. The median imaging follow-up duration was 7.9 months, and the median margin dose was 18 Gy. The maximal diameter and volume of tumors were measured. Histological analysis included 96 patients with non-small cell lung cancers (NSCLCs), 40 with melanoma, 35 with breast cancer, and 29 with other histologies. Almost 50% of brain metastases were NSCLCs and commonly measured less than 6 mm in maximal diameter or 70 mm3 in volume. Thirty-three of 1237 tumors had local progression at a median of 8.8 months. The 1- and 2-year actuarial LC rates were 97% and 93%, respectively. LC of 100% was achieved for all intracranial metastases less than 100 mm3 in volume or 6 mm in diameter irrespective of histology. Patients whose tumors at first SRS were less than 10 mm maximal diameter or a volume of 250 mm3 had improved overall survival (17.1 months vs. 10.3 months, P = 0.02). The authors concluded that an earlier initial detection and prompt treatment of small intracranial metastases may prevent the development of neurological symptoms, decrease the need for resection or the risk of adverse effects from SRS, and improve overall survival. To identify tumors when they are small, routine surveillance brain imaging should be considered as part of the standard of care for lung, breast, and melanoma metastases. This study has two limitations: long-term control rates were not available, and the use and timing of systemic therapies, potentially affecting LC of brain metastases, were not analyzed. The merit of this study is to raise the question of the value of a screening with MRI for brain metastases in asymptomatic patients with solid tumors. It is well documented that certain tumor types, such as HER2+ positive breast cancer, have an increased risk for a marked and earlier metastasis to the brain. Thus, this subgroup could be a good candidate for a prospective validation study before changing the present guidelines. References 1. Sahgal A, Larson D, Knisely J. Stereotactic radiosurgery alone for brain metastases. Lancet Oncol . 2015; 16( 3): 249– 250. Google Scholar CrossRef Search ADS PubMed 2. Baschnagel AM, Meyer KD, Chen PYet al. Tumor volume as a predictor of survival and local control in patients with brain metastases treated with Gamma Knife surgery. J Neurosurg . 2013; 119( 5): 1139– 1144. Google Scholar CrossRef Search ADS PubMed 3. Wolf A, Kvint S, Chachoua Aet al. Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery. J Neurosurg . 2018; 128( 1): 23– 31. Google Scholar CrossRef Search ADS PubMed Intravenous Delivery of Oncolytic Reovirus to Brain Tumor Patients Immunologically Primes for Subsequent Checkpoint Blockade Immune checkpoint inhibitors have been effective in curing a subset of cancer patients, including those with non-small cell lung cancer and melanoma. However, immunotherapies have yet to make inroads in the treatment of glioblastoma (GBM). Agents that target the programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1) axis such as nivolumab were recently shown to be ineffective in recurrent GBMs, and the outcome in primary GBMs is currently being evaluated.1 One important reason PD-1 inhibitors fail is the lack of expression of PD-1 and its ligand PD-L1 in the tumor microenvironment.2 A recent study by Samson used a clever approach to address this problem.3 They reasoned that targeted, virus-mediated interferon expression would stimulate the expression of PD-1/PD-L1 in GBMs and prime them for targeting using immune checkpoint inhibitors. To first establish this condition, the authors injected oncolytic human orthoreovirus, which has previously been shown to infect gliomas, intravenously into tumor bearing mice and showed the expression of reovirus capsid protein and RNA in the xenografts, demonstrating the proof-of-concept that reovirus can reach brain tumors even when administered systemically. They then tested the effects of intravenous administration of reovirus in high-grade glioma or brain metastases patients, 3–17 days prior to undergoing surgery, and found moderate side effects of lymphopenia and flu-like symptoms. But importantly, reovirus administration caused engagement of pathogen recognition receptors and release of interferons in the circulation within two days. Following surgery, the presence of reovirus in the tumor was not only confirmed using a battery of assays, but the authors also found reoviral protein expression in association with Ki67, an indicator of high viral replication in proliferating cells. The authors then used RNA sequencing to examine the differential gene expression between reovirus-treated and untreated GBMs. Interestingly, the expression of CCL3 and CCL4, factors known to recruit CD8+ T cells, and ICAM, an important mediator of vascular interactions of T lymphocytes, were upregulated in reovirus-treated tumors. As a confirmation of the pathological consequences of the differential gene expression, the authors found high levels of infiltrating CD8+ T cells and the presence of CD68+ microglia/macrophages in reovirus-treated tumors. The authors also noted a significantly higher expression of over 5000 interferon-related genes induced upon reovirus treatment, which was inferred as the cause of higher PD-L1 expression in treated tumors. They further clarified this in primary and brain metastatic cell lines in which reovirus treatment was sufficient to cause induction of PD-L1 expression. Furthermore, the expression of PD-L1 was upregulated in immune infiltrates from high-grade glioma patients that were treated with reovirus, and blockade of type I and type II interferons attenuated the induction of PDL-1 in patient-derived glioma cells. Finally, the authors demonstrated that the combined effects of PD-1 blockade and reovirus administration caused significant improvement in survival of mice implanted with GL261 glioma cells. This study overcomes two important challenges in GBM therapy: it demonstrates the ability of oncolytic viruses to penetrate the tumor core without the need for local delivery, and importantly reveals a mechanism by which successful immunotherapy can be achieved in GBM patients. Future GBM clinical trials based on this model are warranted. References 1. Omuro A, Vlahovic G, Lim Met al. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol . 2018; 20( 5): 674– 686. Google Scholar CrossRef Search ADS PubMed 2. Diggs LP, Hsueh EC. Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response. Biomark Res . 2017; 5: 12. Google Scholar CrossRef Search ADS PubMed 3. Samson A, Scott KJ, Taggart Det al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci Transl Med . 2018; 10( 422):pii: eaam7577. Google Scholar CrossRef Search ADS PubMed Therapeutic Targeting of Ependymoma as Informed by Oncogenic Enhancer Profiling With the current focus on precision medicine to tailor disease treatments to individuals based on their tumor DNA, what do we do with the growing number of malignancies for which genomic sequencing has not identified therapeutic targets? The recent Nature article by Stephen Mack and colleagues highlights one such malignancy, that of ependymoma, for which we continue to seek effective targeted therapies.1 Intracranial ependymomas segregate based on anatomic location and are further divided by differences in age of onset, gender predilection, and therapeutic response. Yet, despite advances in understanding the distinct location-specific histological variants, we have made little progress in the treatment of this disease. Radiation remains the standard of care for most variants, with the role for chemotherapy currently under investigation in ongoing large-scale trials. By applying chromatin mapping of 42 primary ependymomas from two non-overlapping multinational cohorts integrated with whole-exome sequencing, whole-genome sequencing, RNA sequencing, DNA copy-number analysis, and DNA methylation profiling, the authors identify essential super enhancer-associated genes on which these tumor cells depend. They identified well over 2000 super enhancers in each of the cohorts, many of which were common to both groups, tumor-specific, and enriched for cancer-associated genes such as PAX6, FGFR1, and BOC. Expectedly, genes such as EPHB2 and CCND1, previously validated as ependymoma oncogenes, also came up on the list.2,3 The authors used RNA interference short-hairpin RNA knockdown time course studies to further elucidate the super-enhancer-associated genes on which ependymoma cells depend, thereby providing potential therapeutic targets. An interesting observation within the molecular subgroups of ependymoma has been the element of lineage specificity reflected in its tendency to present at different ages and in different regions of the brain. The authors built upon the observation that several subgroup-specific super enhancers are restricted or more active within certain regions of the developing central nervous system at specific times to further identify varying levels of gene expression across the subtypes that may offer insight into the lineage programs of this disease. By integrating their combined data with drug interaction databases, the authors offer possible therapeutic leads to inform future trials in ependymoma. References 1. Mack SC, Pajtler KW, Chavez Let al. Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature . 2018; 553( 7686): 101– 105. Google Scholar CrossRef Search ADS PubMed 2. Johnson RA, Wright KD, Poppleton Het al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature . 2010; 466( 7306): 632– 636. Google Scholar CrossRef Search ADS PubMed 3. Mohankumar KM, Currle DS, White Eet al. An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes. Nat Genet . 2015; 47( 8): 878– 887. Google Scholar CrossRef Search ADS PubMed Targeting the Circadian Clock for Cancer and Glioblastoma Therapy The circadian clock is an endogenous biological clock that has a period of approximately 24 hours. It regulates many physiological processes and its dysregulation has been associated with a variety of human pathologies, including cancer. At the molecular level, the circadian clock is driven by two transcriptional complexes that regulate each other’s activity: the clock activators CLOCK and BMAL1 and the repressors PER, CRY, and REV-ERB proteins. REV-ERBs are heme-binding nuclear receptors that act as repressors of the clock as well as of various cancer processes. REV-ERB agonists, such as the pyrrole derivatives SR9009 and SR9011, have been developed. A recent study published in the journal Nature tested the effects of clock repression with SR9009 and SR9011 (SR) on cancer and glioblastoma.1 The study found that SR treatment was cytotoxic to a wide variety of cancer cells lines including glioblastoma and brain tumor-initiating cells but did not affect their normal cell counterparts. This effect was independent of p53 and reactive oxygen species production. However, SR-induced cancer cell cytotoxicity was associated with inactivation of de novo lipogenesis, a hallmark of cancer. In addition, SR treatment inhibited autophagy in the cancer cell lines at an early stage, in part via downregulation of autophagy regulators ULK3, ULK1, BECN1, and ATG7. Further, in vivo studies showed that SR induced cell death and inhibited autophagy in NRAS-induced premalignant nevi in mice skin. As SR9009 is known to cross the blood-brain barrier, its effects on mice bearing established patient-derived glioblastoma xenografts were tested. SR9009 significantly inhibited tumor growth and prolonged animal survival. The SR9009 anti-glioblastoma effects were of similar magnitude to those induced by temozolomide. The study concluded that circadian clock repression with REV-ERB agonists could have anti-tumor effects towards a wide variety of cancers via inactivation of de novo lipogenesis and autophagy. In conjunction with other studies that demonstrated a role for the circadian clock in regulating cancer processes and anticancer drug metabolism (reviewed in2), this study suggests that the circadian clock can be exploited to improve cancer and glioblastoma therapies. References 1. Sulli G, Rommel A, Wang Xet al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature . 2018; 553( 7688): 351– 355. Google Scholar CrossRef Search ADS PubMed 2. Innominato PF, Roche VP, Palesh OG, Ulusakarya A, Spiegel D, Lévi FA. The circadian timing system in clinical oncology. Ann Med . 2014; 46( 4): 191– 207. Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Neuro-Oncology – Oxford University Press
Published: May 18, 2018
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