SNO 2014 Highlights

The following summaries are based on notes taken during presentations at the 19th annual meeting of the Society for Neuro-Oncology, held in Miami Beach Florida, November 13-16 2014.

Wednesday November 12, 2014. Marriot Stanton Hotel

A couple days prior to the beginning of the SNO conference, a “satellite meeting” was held at the Marriot Stanton Hotel, South Beach, Miami. Highlights from these sessions included a talk by Eric Wong of Harvard Medical School and the Beth Israel Deaconess Medical Center. In a presentation entitled “Dexamethasone Exerts Profound Interference on NovoTTF-100A Efficacy for Recurrent Glioblastoma“, Dr Wong presented retrospective data showing that patients treated with Tumor Treating Fields (NovoTTF, now called Optune) in a previous phase 3 trial had better response to this treament when they were taking less than 4.1 mg dexamethasone per day. The patients who had response to the electric fields (TTF) took 1-2 mg dexamethasone on average, while non-responders took higher doses (up to 6-7 mg). When the data was stratified by a dexamethasone intake of 4.1 mg per day, those taking under this amount had median overall survival of 11 months, while those taking more than this amount had median survival of only 4.8 months.

A talk by Kenneth Swanson of Harvard Medical School entitled “Disruption of Cell Division Within Anaphase by Tumor Treating Electric Fields (TTFields) Leads to Immunogenic Cell Death: Implications for Treating Gliobastoma” may shed some light on the reasons for the worse survival outcomes of patients treated with TTF who also took high doses of dexamethasone. In this talk, he described his work showing that NovoTTF disrupts cells as they enter anaphase, at the metaphase to anaphase transition, and made claims that a cytoskeletal protein called septin may be the true cellular target of NovoTTF. He also showed that NovoTTF-induced cell death leads to the exposure of calreticulin and other immunogenic molecules, and that part of the therapeutic effects of NovoTTF may be due to an activated immune response following immunogenic cell death. As dexamethasone in high doses has immunosuppressive effects, this could be the possible cause of the interference with NovoTTF of high dose dexamethasone. Swanson speculated that because NovoTTF partially acts through endoplasmic reticulum (ER) stress, other agents that also induce ER stress, such as celecoxib (Celebrex) may be synergistic with NovoTTF.

Rolando Del Maestro of McGill University presented data showing that MGMT methylation is not a binary positive or negative matter, but instead a single tumour may have different degrees of methylation in different areas. In his talk, called “Preoperative treatment of glial tumors with Temodal looking at variable expression of MGMT in tumor and normal tissue removed at operation” he describes how patients were pre-operatively treated with Temodal (temozolomide, TMZ), followed by MGMT methylation analysis in several different locations in the resected tumour. In one example, there was 0%, 15%, 50%, and 92% MGMT methylation in four samples from the same tumour. The implications are that within a single tumour there are potentially some areas which are more responsive to TMZ chemotherapy (MGMT methylated) and other areas that are resistant (MGMT unmethylated). At recurrence, TMZ resistant subclones may emerge, and this is due to the outgrowth of pre-existent MGMT-unmethylated clones, rather than any changes in methylation status within cells. In terms of MGMT methylation, tumours may be categorized as uniformly methylated, uniformly unmethylated, or mixed (as seen in the example above). This discussion emphasized tumour heterogeneity, and he stated that it is easy to create 100 distinct cell lines representing different subclones from a single tumour.

Thursday November 13, 2014. Loews Hotel

On Wednesday and Thursday, an ancillary meeting called “CNS Anticancer Drug Discovery and Development” was held at the Loews Hotel. The following was one presentation from the second day.

In one presentation, the neuropharmacokinetics of NEO100, a synthesized form of perillyl alcohol, was described. Perillyl alcohol is an intranasally inhaled therapy for glioma which has been tested clinically in Brazil, with positive outcomes. It is said to have direct access to the central nervous system when inhaled nasally, bypassing the blood-brain barrier. According to the data presented here, perillyl alcohol (in the form of NEO100) reaches high levels in the deeply located parts of the brain, most notably the myelencephalon. Peak brain levels are reached in 5 minutes, prior to peak plasma levels, which are reached at 15 minutes. This treatment may therefore have potential in pediatric brainstem gliomas. A phase IIa trial is being planned, at 2 dose levels (96 or 192 mg, four times per day), and will recruit 25-30 first recurrent patients. An IND (Investigational New Drug) application was submitted a week ago.

Friday November 14, 2014. Loews Hotel

Plenary Session 1: Top Scoring Abstracts and Travel Awards

Final analysis of the BELOB trial (A randomized phase II study on bevacizumab versus bevacizumab plus lomustine versus lomustine single agent in recurrent glioblastoma” presented by Martin van den Bent of Erasmus Cancer Institute in the Netherlands. The results of this trial were previously published in Lancet Oncology. The main finding was that combination treatment with bevacizumab (Avastin) plus lomustine extended both progression-free survival and overall survival compared with either monotherapy. The extension of progression-free survival was especially marked after the six-month time point. A phase III trial of the regimen is currently underway in the Netherlands.

“RTOG 9802: Phase III study of radiation therapy (RT) with or without procarbazine, CCNU, and vincristine (PCV) in low-grade glioma: Results by histologic type” presented by Jan Buckner of the Mayo Clinic. The long-term results of this trial were recently summarized in Neuro-Oncology journal by Martin van den Bent. This trial has taken 16 years to bear fruit, starting in 1998, just prior to the initial approval of temozolomide in the treatment of glioma. As trials for low-grade glioma require so much time to complete, the therapies under study may have been superseded by newer therapies in clinical practice by the time the trial is completed. In this trial, which recruited newly diagnosed “high risk” low grade glioma patients over age 40, or with residual post-resection tumour, median overall survival was increased from about 8 years in the radiation only group, to about 13 years when adjuvant PCV was given after radiation. The results of trial will likely change clinical practice for low grade glioma at higher risk for recurrence, though the relative efficacy of temozolomide versus PCV is still an open question, and will remain so until trials currently underway publish long-term results.

Session 2A: Clinical Trials

Correlation of molecular subtypes with overall survival in AVAglio, a randomized, placebo-controlled study of bevacizumab plus radiotherapy and temozolomide for newly diagnosed glioblastoma presented by Carlos Bais of Genentech in South San Francisco. This was an exploratory analysis of survival outcomes of 349 patients enrolled in the AVAglio trial, stratified by molecular subtype (ie. proneural, classical, mesenchymal). Somewhat contrary to expectations, only the proneural/IDH1 wild-type group had a significant survival benefit when Avastin was added to standard treatment, with a statistically significant 5-month increase in median overall survival. In contrast, other subtypes, including the angiogenic mesenchymal subtype, did not seem to benefit from upfront Avastin treatment in terms of median overall survival. The conclusion from this study is that proneural, IDH1 wild-type glioblastoma patients may derive more survival benefit from early Avastin than other subtypes. The reason for the lack of benefit of this anti-angiogenic therapy for the angiogenic mesenchymal subtype is not yet clear.

Survival analysis of patients with a PFS event who did not receive post-progression therapy in AVAglio presented by Timothy Cloughesy of UCLA. This study was based on the same trial outlined in the study above. The overall outcome of this trial is that progression-free survival was improved considerably in the group treated with Avastin added to standard of care, though no overall survival benefit was seen. It could be argued that crossover of placebo-treated patients to Avastin at the time of recurrence could have diluted any signal of increased survival in the upfront Avastin treated group. This study aimed to extract these confounding effects of treatment crossover by studying outcomes of patients who received no further therapy at progression. 24% of all patients in this trial did not receive further therapy at progression, including 105 in the placebo arm and 120 in the Avastin arm. Remarkably, there was a 3.6 month improvement in both median progression-free survival as well as overall survival in the patients receiving upfront Avastin added to standard of care. Dr. Cloughesy also noted that in routine clinical practice, up to 50% of patients do not receive post-progression therapy. The implication of this study may be that patients at high risk for not receiving post-progression therapies may benefit from upfront Avastin. On the other hand, studies have shown that patients who are able to undergo further therapies post-progression may benefit from delaying Avastin therapy until a later time.

Final results from the randomized phase II trial AVAREG with bevacizumab (Avastin) or fotemustine in recurrent GBM presented by Alba Brandes of Bellaria Hospital in Bologna Italy. In Europe, where Avastin has not been approved as it was in North America, use of nitrosoureas for recurrent GBM is the common second-line treatment. In America, Avastin has been commonly used following its FDA approval in 2009. In the AVAREG trial, 59 patients were enrolled in the Avastin arm and 32 were enrolled in the fotemustine arm. The trial was not designed to compare the two arms. The primary endpoint of the trial was percentage surviving at six months (OS6). Though the trial was not designed to be comparative, the patients in the fotemustine arm had better OS6 and overall survival outcomes than the patients in the Avastin arm. This suggests at the least that fotemustine is not inferior to Avastin for recurrent glioblastoma. This will hopefully lead to fotemustine becoming available for North American patients. Fotemustine is administered intravenously, while the more common nitrosourea agent called lomustine (CCNU) is orally administered.

Session 3A: Clinical Trials

ReACT: A phase II study of rindopepimut vaccine plus bevacizumab in relapsed glioblastoma presented by David Reardon of Dana Farber Cancer Institute in Boston. In this trial, EGFRvIII positive patients at first or second recurrence were randomized to receive Avastin plus either the anti-EGFRvIII rindopepimut vaccine, or control (KLH). According to this interim update, six month progression-free survival rate (PFS6) increased from 11% in the control group, to 27% in the rindopepimut group, and this difference was statistically significant. Overall survival increased from 8.8 months in the control group to 12 months in the rindopepimut group, and this was also statistically significant. It was suggested that this survival benefit will continue to improve as the data matures.

A randomized double blind placebo-controlled phase 2 trial of dendritic cell vaccine ICT-107 following standard treatment in newly diagnosed patients with GBM presented by Patrick Wen of Dana Farber Cancer Institute in Boston. The ICT-107 vaccine consists of 6 tumor-associated antigens, two of which are HLA-A1 restricted and four of which are HLA-A2 restricted. HLA (human leukocyte antigen) is the human form of major histocompatibility complex (MHC), a group of antigen presenting proteins at the cell surface. Only patients carrying HLA-A variants 1, 2, or both were eligible for this trial. The trial was stratified by age and MGMT methylation status. The preliminary outcomes of this randomized phase II trial have been published previously. It was found that patients bearing the HLA-A2 allele had the most significant benefit from ICT-107 vaccination, and the preliminary analyses have been confined to this subgroup. Fortunately, HLA-A2 is the most common variant. Overall, median PFS was significantly improved by several months in the ICT-107 group versus the control group. Follow up continues and median survival has not yet been reached in several subgroups. The outcomes for MGMT methylated, HLA-A2 positive patients appear particularly positive. HLA-A1 positive patients do not benefit from the vaccine. A phase III trial of ICT-107 is being planned and this future trial will likely be confined to HLA-A2 positive patients only.

Pilot study of combination of antitumor immunotherapy targeted against cytomegalovirus plus regulatory T-cell inhibition in patients with newly diagnosed glioblastoma presented by Gordana Vlahovic of Duke University Medical Center. In this pilot trial, only patients with gross total resection were included. Patients were treated with vaccine and anti-CD25 antibody treatment beginning during the first cycle of adjuvant TMZ chemotherapy. Seven patients were treated, with a median progression-free survival of 23.5 months and a median overall survival of 30.3 months. The vaccines were well-tolerated. Though this was a small pilot study, the outcomes are promising and a phase II trial is being planned.

Phase 1-2 dose escalation study of VB-111, an anti-angiogenic gene therapy, as monotherapy and in combination with bevacizumab, in patients with recurrent glioblastoma presented by Andrew Brenner of UT Health Sciences Center, San Antonio TX. 23 patients received intravenous VB-111 followed by VB-111 and Avastin at progression, and another 23 patients received VB-111 followed by Avastin at progression. Median survival from initiation of VB-111 was 504 days (16.5 months) in group one and 235 days (7.7 months) in group 2. The data continues to mature, and an phase III trial is being planned.

Friday poster session

VAL-083 is a novel N7 alkylating agent that inhibits the growth of glioma stem and non-stem cultures, including temozolomide-resistant lines Abstract ET-18. Shaun Fouse (formerly of Joseph Costello’s lab at UCSF, currently with Notable Labs) was on hand to explain these results at the Friday poster session. VAL-083 is an alkylating agent which alkylates DNA at the N7 site of guanine, and is not repaired by the DNA-repair enzyme MGMT. It is postulated that VAL-083, as an MGMT -independent alkylating agent, could be even more effective than TMZ, and this is being tested in a phase I/II trial for recurrent high grade glioma recruiting at UCSF, and in Sarasota FL, and Nashville TN. This presentation shows that in vitro concentrations of VAL-083 in the low (1-5) micromolar range have potent effects on cell cycle and cell viability in both glioma stem cells and paired non-stem cell cultures. The drug is also known to cross the blood-brain barrier.

Reactive oxygen species mediate therapeutic response and resistance in glioblastoma. Abstract DR-06. This work was performed at the lab of Liliana Soroceanu at CPMC Research Institute in San Francisco. Liliana, Eric Singer, and Jonathon Judkins were present at the poster session to explain their results. Previous work with cannabidiol (CBD) in murine models of malignant glioma was expanded upon in this new work. In glioma stem cell cultures, cannabidiol induced reactive oxygen species (ROS) and redox stress, which inhibited cell survival and self-renewal but caused an increase in antioxidant response genes as a damage-control mechanism. CBD-induced mesenchymal transition was inhibited by vitamin E, an anti-oxidant, demonstrating the ROS-dependent effects of CBD. Inhibitors of the xCT system sulfasalazine and erastin were used to block this adaptive anti-oxidant response. The strategy going forward is to combine CBD with small molecule regulators of ROS levels, shown to be a synergistic strategy in this preclinical study.

A phase II study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma Abstract AT-33. In this trial, valproic acid was administered together with standard of care, beginning one week prior to radiation. 37 patients were included in the final evaluations. The abstract reports an outstanding median progression-free survival and overall survival of 10.5 months and 29.6 months respectively. One year progression-free survival was 43% and two year progression-free survival was 38%, indicating that very few patients progressed during the second year. In other words, patients who remained progression-free at one year had a high probability of going another year without progression. The abstract does not provide enough patient details to properly interpret these results, which are impressive nonetheless. From the poster, I was able to obtain the following patient details, which give a better perspective on the survival outcomes: 21 patients received Avastin at recurrence, while 15 patients did not receive Avastin. 19 patients received gross total resections, 17 received subtotal resections, and only one received biopsy only. MGMT was methylated in 8 patients, unmethylated in 7 and undetermined in 22. At the time of analysis, seven patients were still alive with disease, and two were still alive without disease. This was a single-arm trial, and the results can therefore only be compared to historical controls. As virtually all the patients underwent surgical resection, the results of this trial should be compared with other surgery-based trials. All things considered, a median overall survival of 30 months is impressive for a patient cohort not stratified by MGMT status. It will be interesting to see if valproic acid is further tested in a randomized setting.

Saturday November 15. Loews Hotel

Session 4A: Tumor Metabolism/ Microenvironment

Identification of the Azole class of antifungals as potent inhibitors of Hexokinase II mediated tumour metabolism in glioblastoma presented by Sameer Agnihotri of University of Toronto. In this study, azole antifungals ketoconazole and posaconazole were identified as potent inhibitors of hexokinase 2, a glycolytic enzyme highly expressed in human GBM. In vitro, these drugs were tested in five different GBM cell lines, and found to be most potent in low oxygen conditions, which predominate in many glioblastoma tumours. Both drugs were futher tested in patient-derived xenograft models at doses of 25 mg/kg mouse body weight. Posaconazole was found to extend survival more than ketoconazole in these models.

Session 4C: Tumor Biology

Demethylating therapy induces differentiation and therapeutic response in IDH1 mutant malignant gliomas presented by Gregory Riggins of Johns Hopkins University. In this presentation, Dr. Riggins summarized previously published data showing that treating mice bearing subcutaneous patient-derived IDH1-mutant tumors with the approved DNA demethylating agent 5-azacytidine can slow growth of these tumors in mice. Previously unpublished data was also shown, revealing that 3 mg/kg doses of 5-azacytidine given to intracranial IDH1-mutant tumor bearing mice only marginally prolonged mouse survival. In the previous work, 5-azacytidine required several weeks before therapeutic effect really kicked in, and this may provide the explanation for the limited efficacy in the intracranial model, in which mice die quickly, thus not giving a chance for the drug to take full effect. Greg Riggins lab is still refining this strategy preclinically, which may give rise to a human clinical trial for IDH-mutant glioma patients in the future.

Session 5B: Clinical Trials

Phase I clinical trial of oncolytic virus Delta-24-RGD (DNX-2401) with biological endpoints: Implications for viro-immunotherapy presented by Frederick Lang of MD Anderson Cancer Center, Houston Texas. This presentation reports on 37 recurrent malignant glioma patients treated with DNX-2401. No adverse events attributed to DNX-2401 were observed. Median overall survival from the start of therapy is 12 months, and remarkably there have been 3 patients (of 25, or 12%) with complete durable responses (tumour disappearance) lasting 42 months, 32 months, and 29 months so far. The therapeutic effects of DNX-2401 appear to be largely mediated by the immune system: dramatic increased enhancement has been observed at one month following therapy, and upon analysis of resected tumour, macrophages and CD8 T-cells were found, with only rare tumour cells. Also, the three complete responders had 10 to 1000-fold increased levels of interleukin 12 (IL-12p70), a cytokine which is one of the main drivers of type 1 cytotoxic immune responses. The 12% complete response rate seen in this small trial is very encouraging. View more details on the Virotherapy page.

Results of a phase 1 trial of an oncolytic polio/rhinovirus recombinant (PVS-RIPO) against recurrent glioblastoma. More details from the phase 1 PVS-RIPO trial were presented this morning by Annick Desjardins. PVS-RIPO is a tumour cell destroying (oncolytic) poliovirus genetically modified so as not to be able to cause poliomyelitis in patients. 15 patients with a median age of 59 and a median KPS of 90 have been included to date. 80% of these patients underwent complete surgical tumour resections. 46.7% had received Avastin therapy prior to enrollment. The earliest two deaths were at 6 months and both of these patients had previously failed Avastin. Dose level 2 was chosen as the optimal dose and five patients have been newly enrolled at that dose level, two to six months ago. Of the eight remaining patients treated for longer than 6 months, four are still alive at 30, 29, 17, and 14 months. A Kaplan-Meier survival analysis on these 8 patients would give 60% survival at 15 months and 40% survival at 20 months. Though this was a phase 1 trial not designed to prove efficacy, these survival outcomes and the long-survival of several patients thus far are very encouraging. View more details on the Virotherapy page.

Administration of Toca 511 to subjects with recurrent high grade glioma undergoing repeat resection presented by Timothy Cloughesy of UCLA. For background information on this therapy, see the Toca 511 & Toca FC page. The data cutoff for the present analysis was September 26, 2014. 34 malignant glioma patients were included. This is a dose-escalation and safety study designed to determine the highest safe dose of Toca 511. Patients were mostly at first or second recurrence, with a few patients at later recurrences. Median survival from trial initiation was 52 weeks (one year) for the entire group, 51 weeks for the GBM patients only, and 59 weeks for the patients at first or second recurrence. The six month progression-free survival rate was 35.3% overall, and 27% for the GBM patients only. In this presentation, 4 partial responses were reported, in addition to 7 patients with stable disease as the best response, and 18 with progressive disease. Dr. Cloughesy stated that virus resistance genes in the tumour were anti-correlated with survival. This could perhaps lead to biomarkers suggesting which patients might benefit from this therapy, as not all patients appeared to benefit.

Interim analysis of the EF-14 trial: A prospective, multi-center trial of NovoTTF-100A together with temozolomide compared to temozolomide alone in patients with newly diagnosed GBM

This presentation by Roger Stupp, just before lunch on Saturday, easily wins the prize as the presentation with the highest impact and the most therapeutic implications which will inevitably lead to a new standard of care for newly diagnosed glioblastoma. For background details on Novocure’s NovoTTF device (now called Optune), see the NovoTTF (Novocure) page. This presentation may also be the most controversial, as many in the neuro-oncology field have been skeptical of this therapy, a skepticism which has now been proven to be unfounded. Essentially, history was made this afternoon as Roger Stupp presented the interim analysis to the audience. Median progression free survival and median overall survival were both improved by three months versus the control group. PFS was 7.1 months in the TTF group and 4 months in the control group. OS was 19.6 months in the TTF group and 16.6 months in the control group. 2-year survival rate was 43% in the TTF group and 29% in the control group. The starting point for these measurements was randomization, which took place after the six week period of combined radiochemotherapy. Average time from diagnosis to randomization was 3.8 months. The improvement in overall survival was statistically significant (p=0.034). This analysis included only the first 315 patients who had at least 18 months of follow-up. Amazingly, the trial was ended early because of the early evidence of success. In the words of Roger Stupp, “a new standard of care for patients with GBM has been established…A new cancer treatment modality has been born.” The presentation was greeted with much excitement and the most robust applause I witnessed at this year’s SNO. It is indeed only a matter of time before NovoTTF is added to radiochemotherapy as a new standard of care for newly diagnosed GBM. This is the first positive phase 3 trial for newly diagnosed GBM since 2005, when the current standard of care (the “Stupp protocol”) was established, and possibly the first non-toxic adjuvant therapy for cancer ever to succeed in a phase III trial for newly diagnosed patients. As a novel, non-toxic therapy, it stands in marked contrast to the traditional triad of cancer therapy: surgery, radiation, chemotherapy. It is being called by some a “paradigm shift”. This therapy will become an essential component of glioma treatment, in combination with other modalities, and takes us one step closer to successful long-term management of the disease.

Sunday November 16. Loews Hotel

Sunrise Sessions

IDH Vaccines presented by Theresa Schumacher, German Cancer Research Center, Heidelberg. For background information on IDH1 targeted vaccines, see A Closer Look at IDH Mutations. This talk summarized the findings that were published by this group in Nature (online June 25, 2014). Theresa Schumacher announced that a trial of their mutant IDH1-targeted vaccine is now registered and should open early 2015.

Session 8C: WHO and Molecular Classifiation Forum

For those interested in spatial and temporal evolution of lower grade gliomas, this session was a real treat.

Integrated genomic analysis of low grade glioma and glioblastoma reveals molecular stratification by IDH status across grades and histologies presented by Roel Verhaak of MD Anderson Cancer Center. This presentation is based on data from The Cancer Genome Atlas Lower Grade Glioma Working Group. A presentation made earlier in the year by Daniel Brat which includes similar information may be viewed on youtube.

Clonal evolution and intratumoral heterogeneity of low-grade glioma genomes presented by Brett Johnson of University of California, San Francisco. This presentation expanded upon previously work published in December 2013 in Science. This group has now collected tissue from 88 patients and has performed exome sequencing on 37 samples. This research has led to both better understanding of clonal evolution of low grade gliomas, as well as identification of a hypermutation phenomenon in a subset of lower grade gliomas treated with temozolomide. This hypermutation profile has the genetic signature of being TMZ-induced. Among the 1000s of novel mutations which typically occur in the hypermutators are new driver mutations in the AKT/mTOR pathway and RB1 pathway which may spur malignant progression to secondary glioblastoma. Hypermutation is caused by mutations in mismatch repair genes, which may evolve as a form of resistance to TMZ chemotherapy. In light of this, TMZ should be used with caution in lower grade glioma patients. Studies are ongoing to determine what percentage of lower grade gliomas are hypermutators in response to TMZ, and whether this response is correlated with the number of TMZ cycles. A case report was also presented, showing that different parts of an IDH1 mutant tumour may harbour different ATRX and TP53 mutations, showing polyclonal parallel evolution. It was also shown that in a hypermutator, there may be hypermutated parts and non-hypermutated parts of a tumour, with the hypermutated parts appearing more aggressive.

The mutational landscape and temporal and spatial clonal evolution to progression in 351 low-grade gliomas presented by Hiromichi Suzuki of Nagoya University and Kyoto University. In this study, whole exome sequencing was performed for 52 low grade glioma samples. The temporal sequence of genetic mutations in lower grade gliomas was examined, concluding that in oligodendrogliomas, IDH1 mutation and TERT promoter mutation are the earliest events, followed by 1p/19q codeletion. For IDH-mutant astrocytomas, the earliest mutational event is IDH1 mutation, closely followed by TP53 mutation. These earliest events are typically followed later by ATRX mutation.

Oligoastrocytoma does not exist: in-situ molecular genetics favors classification as either oligodendroglioma or astrocytoma presented by Felix Sahm of the German Cancer Research Center in Heidelberg. Sahm was presented with the Young Investigator Clinical Research Award for his work. For a detailed summary of this work, see my description in the “Farewell to Oligoastrocytoma” section on the Genetic Overview of Astrocytomas page.

Cell cycle signature and tumor phylogeny are encoded n the evolutionary dynamics of DNA methylation in glioma presented by Tali Mazor of University of California, San Francisco. In this presentation, the contribution of epigenetic alterations to evolution and progression of low-grade gliomas was examined. Patients in this cohort all exhibited the IDH1-mutant associated hypermethylation signature. Of these, patients that underwent malignant progression to secondary glioblastoma acquired a hypomethylation signature in the enhancers of certain genes. This acquired hypomethylation causes activation of genes involved in cell cycle. This study therefore identifies a novel mechanism for progression of lower grade IDH1-mutant gliomas to secondary glioblastoma, via aberrant hypomethylation of key genes involved in the cell cycle. Interestingly, in one sample it was shown that evolution from grade II to grade III occured twice independently in different locations of the tumour.

Genome-wide methylation analysis identifies genomic DNA demethylation during malignant progression of gliomas presented by Kuniaki Saito of Kyorin University and University of Tokyo. This study included 25 matched pairs of low grade gliomas and their recurrences. 20 of these were recurrences at a higher grade (malignant progression). Echoing the previous presentation by Tali Mazor, this study also demonstrated partial demethylation at recurrence of mutant-IDH1 associated hypermethylated tumours. About half of secondary GBM cases that progressed from IDH1-associated hypermethylated tumours showed this partial demethylation.


In terms of practice-changing trials, the positive, statistically significant survival benefit of NovoTTF (now called Optune) added to standard of care for newly diagnosed glioblastoma is clearly the highest impact information presented at SNO 2014. The new standard of care for newly diagnosed glioblastoma will be radiochemotherapy and tumor-treating fields, it is only a question of when, determined by FDA approval. Future trials will have to incorporate these new results, and add experimental therapies onto the prior standard of care plus NovoTTF. Monotherapy should be considered a dead paradigm. Only multi-modal combinational therapy can provide a future for those afflicted with glioblastoma and other gliomas. NovoTTF treatment has been resisted by many in the neuro-oncology community, but the phase III results presented at this year’s SNO conference is going to force a re-evaluation, willingly or not. As a non-toxic cancer therapy which has succeeded in a phase III trial, a new era in glioblastoma treatment has been born. This was the take-home message of Roger Stupp’s presentation. With this novel component in multi-modal combination treatment for newly diagnosed GBM, the future of GBM treatment (and hopefully glioma treatment in general) is now looking a little brighter.