AS has been custom since its founding, NBTS sponsors and attends the Society for Neuro-Oncology (SNO) Annual Meeting. SNO is the top professional society for neuro-oncology research and clinical care globally. This yearly conference provides breaking news, analysis, and discussion of the emerging trends and latest scientific discoveries in the field of brain tumor research and drug development. The 2016 SNO Annual Meeting took place Friday, November 18th – Sunday, November 20th.
Here we report to you on some of this year’s highlights, broken-down into five main buckets:
Molecular Classification of Brain Tumors (World Health Organization Updates Classifications)
As previously reported in early 2016, the World Health Organization (WHO) updated its classification system for brain tumors, including for the first time molecular characteristics (genetic information) along with traditional histopathology (how a tumor looks under a microscope). The updated classifications allow for more accurate diagnosis, prognosis, treatment planning, and clinical trial stratification in the field of brain tumor research and clinical care. These updates and their implications for both adult and pediatric brain tumors were much discussed at SNO 2016, with three presentations dedicated to the topic during Friday morning’s Plenary Session along, combined with additional lunch-time breakout sessions on Friday as well as Saturday and with considerations sprinkled throughout many other presentations throughout the weekend.
Many of this year’s presentations and reports continued to highlight the emerging importance of what is known as “epigenetics.” Put simply, “epigenetics” in cancer research refers to molecular changes found in tumor cells due to changes in gene expression that are not caused by alterations to the DNA sequence (i.e. gene mutations).
Cancer has long been recognized as diseases caused by genetic abnormalities. But research is beginning to show that epigenetic changes, such as alterations to the process in which a cell’s DNA sequence is decoded, or read (called transcription), and how certain molecules in cells turn genes on and off without changing the DNA sequence can also initiate and fuel tumor growth, often in combination with genetic mutations.
During Saturday morning’s two keynote presentations, both Drs. Joseph Costello of the University of California, San Francisco and Bradley Bernstein, an institute member at the Broad Institute and a professor in the Department of Pathology at Massachusetts General Hospital and Harvard Medical School, discussed how a genetic mutation can initiate (cause) epigenetic changes such as DNA methylation and histone modification, which ultimately prevent the cell from functioning properly and driving tumor growth (effect). For example, research has found that the well-known mutation to a gene called IDH1 can cause glioma cells to produce an enzyme that subsequently interferes with how DNA in a cell is read (again, transcription) by causing changes to histones, which package the cell’s DNA. These presentations were aptly named, “The Parallel lives of mutations and epimutations during tumor evolution” and “Epigenetic mechanisms of glioma initiation and evolutions,” respectively.
Earlier the same day, NBTS-funded researchers Dr. Mario Suva co-led a “Sunrise Session” called Glioma Stem Cells and Epigenetics – From Biology to Treatment,” in which he discussed a new paper (which NBTS provided funding for) that discovered cancer stem cells (CSC’s), defined as cells that can self-renew and differentiate into multiple types of cells found in tumors, play a role in the development and progression of tumors by a hierarchy related to developmental pathways and epigenetic programs.
Epigenetics also played a major role in many of the studies presented during the intensive (1:30-5:00PM) pediatrics session Saturday afternoon.
Everyone can relate to the value of a good photo. Whether it’s a family memory, a landscape from travel/sight-seeing, a headshot for work, etc., the proverbial “Kodak Moment” can hold important value. The same is true when researchers and doctors need to capture an image of a brain tumor – a good picture can “speak a thousand words.” Unfortunately, because of the brain’s complexity a good image that tells the whole story of a tumor, is harder to come by than one might think. This is why brain tumor imaging was the subject of multiple sessions at SNO 2016, and an imaging study was presented as a “Top Scoring Abstract” and award-winning abstract during Saturday’s Plenary session. NBTS and our partners in the Jumpstarting Brain Tumor Drug Development Coalition also held a side-meeting at SNO, a day prior to the main meeting program beginning, to discuss our imaging endpoints effort. Beyond that, brain tumor imaging was the topic of two sessions on Saturday and a Sunrise Session on Sunday.
The value of a good image as it relates to brain tumors, is important in helping researchers and doctors understand if a treatment is successfully shrinking a patient’s tumor. This can affect both individual treatment as well as clinical trials. In regular clinical care, a patient’s neuro-oncologist can use neuro-imaging to monitor if that patient is responding to the therapies being given, and use that information to change treatment course if needed. In clinical trials, if researchers can use neuro-imaging to accurately determine if the experimental therapy is shrinking patients’ tumors, decisions can be made faster about the potential effectiveness of that treatment being evaluated – speeding clinical trials up so promising new drugs can get to the marker faster, while saving time, money, and lives.
Much of the work presented at SNO centered around studies trying to determine and/or develop new ways to get that clearer picture to truly tell if a tumor is responding to treatment.
For example, in a study led by Dr. Benjamin Ellingson of UCLA, a group of researchers were able to demonstrate that by measuring the volume of the portion of the tumor that is seen on MRI and CT images that is enhanced by a contrast agent, researchers can strongly predict early on, before therapy, if an experimental drug is going to increase patient survival. The group concluded that “contrast enhancing tumor size should be considered in clinical trial design and during interpretation of therapeutic benefit.”
In the aforementioned study that garnered “Top Scoring Abstract” honors, also showed how imaging may be able to help provide less invasive means for diagnosing tumors. The presentation, titled, “18FET-PET uptake dynamics serves as an additional imaging biomarkers in astrocytomas with IDH1/2 mutation and no LOH1p/19q,” demonstrated that using an advanced form of PET scan imaging, researchers may be able to differentiate between high-grade (Grades III and IV) and low-grade (Grades I and II) glioma without a biopsy. If this method is further developed, it would allow for the possibility of low-grade glioma patients to potentially delay or reduce the need for invasive and/or harsh treatments.
This year, so many clinical trial updates were presented at SNO, that the main session for the updates ran from 1:30-5PM on Friday.
Long-Term Data on Optune
The most complete report was given on Optune, with Dr. Roger Stupp of the University of Zurich Switzerland reporting that long-term follow-up of patients in the clinical trial of Optune (which was stopped early at the recommendation of an independent review committee, because an interim analysis of data showed the device to be sufficiently promising to submit the device for approval to the FDA) that had led to its approval in October of 2015. Though Novocure officially stopped the trial in November of 2014 and gained approval for the use of Optune – in combination with surgery, radiation, and temozolomide (Temodar) – the company and trial researchers continued to follow-up on patients who had participated in the study. These long-term data confirmed what had been determined by the interim analysis: that adding Optune to temozolomide, following surgery and radiation, extends survival in newly diagnosed glioblastoma patients. Final analysis specifically found that median overall survival time for patients in trial using Optune was 20.8 months, while patients only getting temozolomide had median survival of 16 months. Further, 17.3% of patients in the Optune arm were alive four-years after treatment, compared to only 10.4% of the temozolomide-only patients.
Immunotherapy has been an emerging topic in neuro-oncology for a few years now, and the field has progressed to a point where many of the trial updates presented at SNO 2016 were on potential immunotherapeutic approaches for treating gliomas.
However, because it was long considered that immune cells didn’t enter the brain like they do other tissue and organs, immunotherapeutic approaches in neuro-oncology are behind where they are in some other cancers. As such, much of the data presented on immunotherapies at SNO 2016 were very preliminary in nature. Yet, the positive news was that for almost all of the trials, early data was showing that this promising treatment modality was showing feasibility.
For example, a type of immunotherapeutics called “checkpoint inhibitors” have generated a tremendous amount of excitement for the results they have produced in cancers like melanoma, lung, head and neck, and certain blood cancers. In many cases, there are already checkpoint inhibitors approved to treat these cancers, but they are still in early-phase clinical trials for brain cancer. But, encouragingly, three different check-point inhibitors – nivolumab (Opdivo), pembrolizumab (Keytruda), and durvalumab (MEDI4736) – all showed that they were safe and tolerable for glioblastoma patients, and though phase 1 trials aren’t designed to necessarily measure effectiveness, all showed early signals of efficacy. The conclusion for all these trials, was that these early results are good enough to warrant moving the drugs onto larger trials.
Closely related to immunotherapy is a treatment modality called “gene therapy.” A novel gene therapy regime called Toca 511 and Toca FC, developed by Tocagen (note: NBTS provided funding to Tocagen to help with the development of Toca 511 and Toca FC) has shown early encouraging results which were presented at SNO 2016. Like the checkpoint inhibitors, treatment of high-grade glioma patients with Toca 511 and Toca FC was shown to be safe and tolerable in a phase 1 trial, with preliminary efficacy data also encouraging and warranting further trials.
Trials for lower-grade gliomas
In addition to the trials discussed above, which mainly focused on glioblastoma and other high-grade gliomas, there was also a number of interesting trials that provided important data that will ultimately help determine how to best treat low-grade gliomas (again, Grades I, II and in this case even III). Of particular note, were the so-called CANTON and TAVAREC trials, as well as data regarding the potential application of IDH inhibitors.
The CANTON trial sought to determine the role of both concurrent (given with radiotherapy) and adjuvant (after radiotherapy or chemo/radiotherapy) temozolomide treatment for non-1p/19q deleted anaplastic glioma patients. Data presented at SNO 16 from an interim analysis of the CANTON trial showed that the use of adjuvant temozolomide does improve the survival rates of patients with non-1p/19q deleted anaplastic gliomas. This is the first time a well-controlled clinical trial has shown that adjuvant temozolomide has benefit to these Grade III gliomas, thus dictating that radiation alone is no longer a sufficient treatment for these patients. The trial is scheduled to reach a conclusion in 2024 and during the remaining part of the trial, results will be generated to determine whether concurrent RT and TMZ provide superior clinical outcomes over non-concurrent TMZ treatment.
The TAVAREC trial assessed the significance of treating recurrent Grade II and III gliomas with the anti-angiogenic drug bevacizumab (Avastin). The data presented from this trial showed no significant improvement in either overall survival or progression-free survival by combining bevacizumab to temozolomide for the treatment of Grade II and III glioma patients whose tumors have come back after initial treatment with surgery and radiation. Thus, bevacizumab appears to have no utility for these patients – which is different from even GBM patients, who, while not experiencing better overall survival in combining bevacizumab with temozolomide, do experience small benefits in progression-free survival. Researchers are, however, still investigating whether any molecular subgroups benefit more than others from adding bevacizumab. (A separate study presented at SNO also found similar results in pediatric and adolescent patients with high-grade gliomas in that bevacizumab did not improve survival data).
Finally, Dr. Ingo Mellinghoff of Memorial Sloan Kettering Cancer Center, and a Defeat GBM Research Collaborative principal investigator, presented data on so-called IDH1 inhibitors. Mutations to this gene, occur in many grade II and III glioma patients (and even smaller subsets of high-grade glioma patients). As discussed above, these mutations can result in a “re-wiring” of glial cells, including an altered metabolism, which ultimately can drive tumor formation and progression. But up to now, attempts to target IDH1 as a treatment approach have been unsuccessful. At SNO 2016, Dr. Mellinghoff showed that a new drug being developed called AG-120 is showing early promise targeting this mutation.
“AG-120 is well tolerated and 42% of patients remained on AG-120 as of data cut-off,” said Dr. Mellinghoff. “AG-120 has the potential to help a large number of patients with IDH1 mutations.”
Dr. Mellinghoff concluded that further evaluation of inhibitors of IDH in glioma is warranted, and noted another potential new drug, AG-881, is also under phase 1 investigation in glioma patients with IDH1 and IDH2 mutations. (Also discussed was a first-in-man trial of the IDH1 peptide vaccine targeting the IDH1R132H mutation, called NOA-16).
Scattered throughout the sessions at SNO 2016, there were many fascinating pieces of information, spanning the entire spectrum of brain tumor research, treatment, and clinical management. There were sessions and presentations that focused on better monitoring of “quality of life” related impact of brain tumors and other patient-centric measures (e.g. predicting toxicity in patients, language recovery, sexual dysfunction, palliative care, and long-term neuro-cognitive and physical effects); presentations on the impact of patient, caregiver, and family camps for brain tumor patients, as well as brain tumors caregivers’ physical and emotional health; talks on the connections between pediatric brain tumors and issues economic attainment later in life and development of “late-effects” like ADHD; and discussion of how to potentially use smartphone apps to collect data during clinical trials and treatment.
Some especially interesting discovery research also included:
Studies on the risk related to developing brain tumors in individuals with Neurofibromatosis, Li-Fraumeni Syndrome, and other genetic disorders.
The identification of a protein called “fibulin-3” as a target for a type of immunotherapy called CAR-T Cell therapy, the first demonstration of an “extracellular matrix” – meaning molecules secreted outside the cell – target for this type of treatment.
The identification of more epigenetic targets to consider for potential drug development, like EZH2 (a histone-modifying enzyme) inhibitors for Grade III glioma patients without IDH mutations and the HMGA2-CD44 pathway in pediatric and adult high-grade gliomas (including DIPG).
Discussion of how the immune environment around brain tumors seems to change between primary and recurrent glioblastomas, necessitating more research on the topic.
When the 2016 Society for Neuro-Oncology Annual Meeting officially closed on Sunday afternoon, the meetings organizers told a gathered crowd how more than 2,350 people attended the conference (200 more than in 2015) and 1,024 abstracts were submitted (a record number, and 100 more than last year). This meeting grows every year and truly is commensurate with how the fields of neuro-oncology, neuro-surgery, neuro-radiology, neuro-pathology, neuro-imaging, and any other related “neuro-“ continue to mature and make greater strides each and every year.
SNO’s current president, Dr. Antonio Chiocca of Brigham & Women’s Hospital and Harvard Medical School, may have captured this spirit best in his presidential address when he deployed the football metaphor, “moving the chains,” (complete with photos of Tom Brady!) to describe how the field was making progress against brain tumors. Dr. Chiocca described how this year’s meeting main theme was “understanding our enemy better” and how much of the data discussed at SNO, did indeed, help us understand brain tumors at a deeper-level, which will ultimately lead to breakthroughs that can help patients. He described how the steps that are happening in the field as steadily “moving the chains” down the football field, keeping the drive alive on the march to the endzone for a touchdown. While we would all love to see, a “Hail Mary” pass, the complexity of these tumors makes that prospect difficult, but in the meantime we’ve seen the approval of Optune; the encouraging emerging results of immunotherapies and certain precision medicines or targeted therapies; surgical and radiation techniques improving our ability to remove more of tumors; better understanding of how, when, and on whom to use chemotherapies like temozolomide and anti-angiogenic inhibitors like bevacizumab.
But just as in real football, when you get closer to the endzone (the “redzone”) the stakes get higher and the level of difficulty increases. We must continue to push forward with increased determination and fervor, because for brain tumor patients, there is no other alternative than a touchdown. We must find a way(s) to cross the goal line.