Twelve questions to answer that will drive the brain tumor research field forward
“I think that this year is even more accelerated in progress than last year. Lots of new things, lots of new possibilities…we really are all pushing together and trying to get to the top of the mountain.”
With those words, Dr. Web Cavenee of Ludwig Cancer Research began his recap of the 2017 National Brain Tumor Society Scientific Summit during the program’s wrap-up session and closing remarks.
Dr. Cavenee, a pioneer in the field of brain tumor research, went on to highlight a dozen questions that arose from the day’s candid and open set of conversations among top minds from different sectors of neuro-oncology. These discussions ranged between a number of the most pressing issues, challenges, and opportunities facing the field and how to move forward toward better treatments and cures.
Dr. Cavenee offered that these questions were extremely important to the field’s potential future progress, could be used as “action items,” and that they could perhaps be addressed “relatively quickly, and would really increase our ability to move forward.” He likened the field’s prospective pursuit of these questions to plotting a “new map” for greater progress for patients – borrowing a metaphor used in an earlier discussion led by his colleague at the Ludwig Institute for Cancer Research, Dr. Paul Mischel, regarding his paradigm-shifting ecDNA discovery.
SESSION 1 – Tackling Adversity: Heterogeneity and Tumor Evolution
Drs. Joseph Costello (University of California, San Francisco), Bradley Bernstein (Massachusetts General Hospital and the Broad Institute of Harvard and MIT), Cavenee, and Kristin Swanson (Mayo Clinic)
Incorporating the program’s Keynote Presentation by Dr. Bernstein on how genetic and epigenetic factors converge to drive the evolution of glioma brain tumors, this session examined the various factors that could be driving and/or contributing to how tumors acquire differing sets of mutations and other molecular alterations over time and, potentially, as a response to treatment. This evolution and heterogeneity makes gliomas, particularly high-grade gliomas like glioblastoma, very complex and very difficult to treat.
Based on the dialogue and highlights from the panel, Dr. Cavenee queried:
- Can new technologies like so-called “single-cell” analysis of a tumor’s epigenetic and genetic landscape be incorporated into glioma clinical trials?
- This would give the field the ability to possibly see if a drug being tested was actually successful at wiping out cells with its target mutation or alteration, but that the tumor’s diverse (heterogeneous) population of cell types allowed the tumor to rely on its other cells – driven by a different set of mutations or alterations – to keep growing.
- Can “single-cell” landscape analysis then be combined with new and advanced imaging techniques to predict how a patient is going to respond to a given treatment?
- These new technologies could, together, help doctors better understand which patient(s) will respond to which treatment(s) by offering a more in-depth picture of their tumor and its various cell populations and their likelihood to be more (or less) aggressive.
- Does the heterogeneity found in glioma tumors impact this field’s ability to utilize immunotherapy – as so many other cancer fields are now doing with some striking successes?
- Similar to the idea of the first question for this session, it would be important for the field to know if the reason why neuro-oncology hasn’t seen as much success to-date with immunotherapies as other cancer types have is because of the diversity of cell types found within these tumors. Or conversely, if tumors that have a lot of heterogeneity might give even more credence to pushing forward with immunotherapy, because to-date immunotherapy has been shown to be more effective against tumors with high-numbers of mutations.
This session discussed how different mutations and alterations commonly found in gliomas can actually “re-wire,” or “re-program,” various other elements of a glioma cell’s environment and functions, including the cell’s metabolism and microenvironment (surrounding blood vessels and other types of cells). This can include changing how, and how much, glioma cells gobble up nutrients to fuel their growth. Glioma cells have been found to become dependent or “addicted” to these nutrients – which would have important implications for developing new treatment strategies. Finally, this discussion led to the potential importance of where these mutations and alterations are found within cells (again, the ecDNA topic mentioned above), and how that could relate to treatment resistance in glioma patients. [More on some of these concepts here]. These observations begged the following questions:
- Can oncogenes (genes that, when altered, have the propensity to cause cancer) “jumping onto” ecDNA be prevented or stopped?
- If oncogenes could be prevented from jumping onto ecDNA – which are small, circular fragments of DNA found outside of chromosomes, where DNA usually is found – it could make tumors easier to treat. This is because, as cells divide and replicate when DNA is passed down from chromosomes, it occurs in a more neat and orderly fashion (or linear fashion). But when DNA is replicated from ecDNA it happens more haphazardly, meaning some daughter cells will inherit certain sets of mutations and alterations, while others might get entirely different sets. This contributes to the heterogeneity discussed above, and makes tumors more complex and thus difficult to treat.
- Can a tumor’s microenvironment – and what’s in it and how it changes over time – be correlated with patients’ response to treatments?
- Right now, the field has both “knowledge” and “measurement” gaps when it comes to analyzing the tumor microenvironment’s impact on tumors’ resistance abilities and how that relates to patients’ response to treatments. However, Summit participants believe that new and emerging pathology and diagnostic platforms could be used to analyze if/what effect it could have.
- Can the field catalogue all the specific dependencies that tumors develop, especially those that occur in response to treatments? Can the field then figure out if these have predictive value in understanding what patients are most likely to develop resistance to a given treatment? And does it matter if they occur inside the tumors cells or in the tumor microenvironment?
- Understanding these areas better could open up the pharmacopeia for GBM patients beyond traditional cancer drugs. Since just getting drugs across the blood-brain-barrier (more below) and to the tumor is a major issue in neuro-oncology, the field is limited in which traditional anti-cancer drugs it can realistically expect to work – as most cancer drugs are specifically designed to not be “brain penetrable.” Thus, identifying the ways tumor cells take up and utilize nutrients to foster their rapid growth, and understanding how cells may become dependent on specific enzymes, proteins, and other molecules that are not themselves cancer-causing or cancer-promoting but fuel tumor growth nonetheless (“non-oncogene addiction” or “non-oncogene co-dependency”), is a potentially very important area for study and exploitation. It could open up the potential number, and types, of drugs which could be tried for brain tumor patients beyond traditional cancer drugs.
SESSION 3 – Maximizing Opportunities: Therapeutic Strategies and the Blood-Brain-Barrier
Drs. Patrick Wen (Dana Farber Cancer Institute), Howard Fine (Weil Cornell Medical Center), Alan Olivero (Genentech), Kathy Warren (National Cancer Institute)
The blood-brain-barrier is our body’s natural protection to prevent potentially harmful toxins, pathogens, and chemicals from entering this vital organ. However, when it comes to treating tumors in the brain, this also means that it is hard for many traditional anti-cancer drugs to even get into the brain and to the tumor, as most are specifically designed not to get in. Therefore, it is important for the field to better understand if a drug can ever reach its target at a potent enough concentration to have the therapeutic effect that is intended before a lot of resources are devoted to it in a large clinical trial.
- How can the field encourage biopharmaceutical companies to develop drugs that cross the blood-brain-barrier?
- The more anti-cancer drugs that can be at least modified to cross the blood-brain-barrier, the more possibilities and options researchers will have to test different, and potentially new and effective treatments for brain tumors. Further, researchers and doctors will be able to better understand if a clinical trial failed because the drug is truly ineffective, or if it was just that not enough of the drug made it to the tumor.
- Can the mechanisms that the brain uses to “spit out” drugs be modified to allow higher concentrations of drugs to stay inside the brain long enough to be effective in attacking the tumor?
- One way the brain-brain-barrier performs its duties is through “efflux pumps” which “spit out” harmful chemicals that are trying to slip through its defenses. If researchers can figure out a way to, perhaps, temporarily “turn-off” these pumps, it could allow enough drug to get across the barrier and to the tumor, again opening up the pharmacopeia that could be tested in brain tumors.
- Should the field support the development of new early-phase clinical trial consortium?
- Ultimately, even if the first two questions are adequately answered by the field, before moving a drug into larger clinical trials it will still be critical to develop better ways to measure how much of a given experimental drug is getting across the blood-brain-barrier and to the tumor. This could potentially be accomplished in an efficient manner by developing a first-class early phase clinical trial consortium that can provide this type of analysis before recommending drugs move forward into larger trials.
SESSION 4 – Maximizing Opportunities: Immune System and Immunotherapy
Drs. David Reardon (Dana Farber Cancer Institute), Michael Lim (Johns Hopkins), Cassian Yee (MD Anderson Cancer Center)
According to Dr. Reardon, a brain tumor immunotherapy expert, there are already nine different immunotherapies approved by the FDA to treat certain types of cancers. Specifically, these drugs are currently approved of use in 13 different cancers. Unfortunately, malignant brain tumors are not one these 13 cancers that have seen an approval for one or more of these nine cutting-edge treatments. This session discussed some potential reasons why immunotherapies have yet to demonstrate significant or widespread success in neuro-oncology, as well as potential strategies to boost and enhance the effectiveness of these types of treatment for brain tumor patients.
- What is it that the responders to immunotherapy have that the non-responders don’t?
- Though immunotherapies haven’t demonstrated widespread success in treating brain tumor patients to-date, there have been some anecdotal reports from individual patients of really encouraging and positive responses to these treatments – including some long-term survivors. So if researchers can figure out what it is about the biology (and the characteristics of their tumors) of those that did respond really well to these treatments, it could help inform treatment strategies and decision making (including selecting patients for clinical trials) in the future.
- Are there things the field can try to reduce brain tumors’ ability to suppress the immune system around it? Of the different tactics that tumors use to evade the immune system, which are the most important to target? Could we figure out how to make a “cold” tumor “warm enough” for immunotherapy to be more effective?
- Currently, brain tumors are considered “cold tumors” when it comes to their ability to interact with the body’s immune system. Brain tumors seem to inherently have multiple mechanisms that suppress the surrounding immune system. Additionally, there are not as many lymphocytes (a type of cell that is part of the immune system) surrounding brain tumors as there are found around other cancerous tumors, and the microenvironment of many aggressive malignant brain tumors like glioblastoma are hostile to, perhaps, the most important components of our innate immune system: T-cells. So how could researchers use treatments to make the environment around brain tumors “warm” enough to induce our body’s natural defense systems to attack these tumors. Strategies could include harnessing combinations of therapies to address the various layers of immunosuppression and the factors needed to generate an immune response in brain tumors.
- Can the field figure out how to better deliver CAR T-cell therapy to brain tumors, and keep the modified T-cells at the tumor long enough for maximum effect?
- The first big type of immunotherapy to steal headlines were so-called “immune checkpoint inhibitors.” These treatments “release the breaks” (immune checkpoints) on the body’s immune system to allow it to attack tumors. The newest “hot” area of immunotherapy research is a treatment method dubbed: “CAR T-cell Therapy.” In this approach, patients’ own T-cells are extracted from their blood, engineered to identify and fight tumors, and re-infused back into the patients’ blood stream to make the attack. However, as mentioned before brain tumors tend to live in an environment that is very hostile to T-cells. If researchers can find a way to get these modified T-cells to the tumor in big enough numbers, the chance of this type of treatment approach working in neuro-oncology will increase significantly.
Following the Summit, Dr. Al Yung of MD Anderson Cancer Center and National Brain Tumor Society’s Distinguished Scientific Advisor, who facilitated the Summit’s scientific program, compared Dr. Cavenee’s set of questions (or, really, action items) to, “a guide for a national agenda for the next few years for brain tumor research funding.”
In addition to the panelists, presenters, and speakers, the Summit featured roughly 100 other leading experts from across sectors of brain tumor and brain cancer research – government, industry, academia, biomedical and scientific research, patients, and advocates – sharing a room with the sole purpose of addressing the biggest barriers to discovering and developing new treatments and a cure.
The four panels and discussion topics represented areas of major importance to bridging the gap between science and increasing patient survival, shaped the day’s agenda and conversations. These sessions included a morning program of robust conversations on critical areas impeding progress that the field is attempting to deal with as a whole, followed by the afternoon sessions looking at some of the most promising areas of research to address unmet needs in neuro-oncology.
“This year’s Summit was particularly impactful, as it generated collective ideas and areas of focus to move this field forward to discover and develop much needed new and better treatments for brain tumor patients,” said Dr. Yung.
NBTS’ CEO, David Arons, weighed in further in a press release following the Summit, saying, “We were encouraged with the level of dialogue and debate, and believe the day’s program offered a glimpse at the real, tangible progress being made currently in the field, as well as identified the key barriers that still need to be addressed in order to find a cure for many types of brain tumors.”
Following the main scientific program, a “poster” session was combined with a reception to allow for more sharing of information and discussion. Scientific poster presenters included NBTS-funded researchers: Drs. Frank Furnari (Ludwig Cancer Research), John de Groot and Erik Sulman (MD Anderson Cancer Center), Mellinghoff, Mischel and Tim Cloughesy (UCLA), Daniel Brat (Northwestern), Elizabeth Claus (Yale/Brigham and Women’s Hospital), Robert Jenkins (Mayo Clinic), Roel Verhaak (Jackson Laboratory); and Michael Prados (University of California, San Francisco).
The Summit then concluded with a dinner program and awards ceremony. Honored during the awards ceremony were, 2017 NBTS Achievement recipients:
- Advocate of the Year – Patti and Ron Gauvin; NBTS Volunteer State-Lead Advocates for New Hampshire
- Community Leadership Award for Volunteerism – Michael Wenger; Volunteer designer of the NBTS Clinical Trial Finder
- Community Leadership Award for a Colleague Organization – Society of Neuro-Oncology (SNO)
- Feldman Founder’s Award for Adult Brain Tumor Research – Dr. G. Yancey Gillespie, University of Alabama at Birmingham
- Ross Founder’s Award for Pediatric Brain Tumor Research – Dr. Michael Prados, University of California, San Francisco
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