Chasing impossible: MIT-DFCI Center for Glioblastoma Systems Biology hosts inaugural Glioblastoma Tumor Microenvironment Symposium
Researchers from across the country convened to discuss novel methods of curing the disease
Veronika Moroz–The Tech
For most cases, it starts with a headache.
Untreated, it can progress to seizures and changes in personality. By the time symptoms become severe, an MRI scan will reveal the cause: a mass of brain cells that won’t stop growing, pushing against and, in some cases, invading and destroying healthy tissue. A glioblastoma.
With 110,000 new cases diagnosed each year and a survival rate of around one year, glioblastoma is not only the most common form of brain cancer, but also the most deadly, says Dr. Forest White, Professor of Biological Engineering.
It’s an “impossible problem,” White says. But to him, that’s what makes it so interesting.
White worked as a Senior Research Scientist of the biotech company MDS Proteomics before joining MIT as an Associate Professor of Biological Engineering in 2003. At MIT, he met a neuro-oncologist who described his experiences treating glioblastomas. “Almost all of his patients died because of the disease, despite their best efforts,” White recalled. “As a scientist, I thought this was completely unacceptable and that we absolutely have to do something.”
On March 27, the MIT-DFCI Center for Glioblastoma Systems Biology hosted the Glioblastoma Tumor Microenvironment Symposium. Organized primarily by White and Isadora Deese, administrative assistant of the White Lab, the symposium featured presentations from
specialists from across the country on topics ranging from cutting-edge treatments and better models for clinical trials to methods of accelerating the fight for a cure.
Defining the challenge
Cells from the main tumor spread out, or disseminate, into different parts of the brain, where they are free to regrow. However, they are hard to treat due to being surrounded by layers of healthy tissue. One step towards curing this disease is figuring out how to target these disseminated cells.
White’s presentation featured the work of one of his former postdocs, Ryuhjin Ahn, who developed the Investigating Signaling Networks in Heterogeneous Tissues (INSIGHT) protocol to accelerate characterization of these cells.
INSIGHT works by freezing samples of the brain, and then slicing the brain and preserving the cells in chemicals so they can be analyzed. “With this approach, we can now quantify how these disseminated cells are responding to different therapies,” White said.
This approach is particularly impactful because of how diverse the tumors can be. “Every single tumor looks different from another one,” said Antonio Iavarone, Professor of Neurological Surgery, Biochemistry, and Molecular Biology at the University of Miami. Iavarone’s talk described how the tumor cells and the tissues around them change as the glioblastoma progresses.
The tumor itself is also immunosuppressive, meaning that it hijacks the body’s defenses so it cannot be identified as a threat. One particular immune cell, the glioblastoma-associated macrophage (GAM), plays a pivotal role in cancer progression.
“GAMs comprise about 30% of human [brain] tumors, and they drive tumor progression, therapeutic resistance and immunosuppression,” White highlighted. That’s why White Lab graduate student Yufei Cui is working on identifying what makes GAMs suppress the immune response to the tumor instead of activating it. “Using this information, you can start identifying the treatment modality that we might want to use to target some of these macrophages after they've interacted with tumor cells,” White said.
Developing new treatments
For over 20 years, the standard procedure for treating glioblastomas has been removing the tumor by surgery, and then treating the patient with radiation or chemotherapy to kill the remaining cancerous cells.
However, tumor recurrence is common, according to Ennio Antonio Chiocca, Professor of Neurosurgery at Harvard Medical School. Chiocca’s solution involves oncolytic immunoactivation: injecting a modified, non-pathological version of a herpes virus into the tumor in order to enhance the body’s natural immune response against it. The virus, CAN-3110, went through an initial round of clinical trials in 2023. It was found to be non-toxic to humans and was associated with improved survival rates for certain types of tumors.
However, according to Natalie Artzi, a researcher at the Institute for Medical Engineering and Science (IMES) at MIT and Associate Professor at Brigham and Women’s Hospital, to really prevent tumor recurrence, you “need to train the immune system to help us eliminate the tumor.”
“This six week gap between surgery and chemo radiation really facilitates the local spread of the tumor,” Artzi said in her presentation. Her lab is working on a treatment that involves removing the tumor during surgery and then spraying the cavity with a thin layer of a hydrogel designed to slowly release immunoactivating medicine into the remaining tissue.
The treatment is particularly effective because it bypasses the blood-brain barrier, which is the body’s way of preventing most substances from entering the brain. “Something like 97% of the approved drugs do not cross the blood-brain barrier,” White told The Tech. “Those cells basically hide behind that barrier and are unaffected by these treatments.“
Artzi’s solution allows scientists to use any drug of interest, and her lab has even designed the hydrogel to release the drug more gradually. In preliminary trials, injecting mice who have glioblastoma with the hydrogel led to 80% of the mice being “completely cured.”
Another novel solution is not attacking the tumor cells directly, but rather slowing down the progression of glioblastoma in the brain. Glioblastoma cells can disseminate in other parts of the brain at very high speeds — a whole hemisphere could be taken over by glioblastoma cells in as little as two months — and proliferate in the surrounding brain tissue, impacting other cognitive functions. But the exact mechanism of how the glioblastoma cells move and ultimately reach other parts of the body is still not well understood.
Through their efforts, University of Minnesota Biological Engineering Professor David Odde and his team were able to develop a model that demonstrated how glioblastoma cells move by using molecular clutches to “stick” to the surface of the brain and pull the main body of the cell where it needs to go.
Armed with this better understanding of the diffusion mechanism of glioblastoma, Odde and his team started looking at potential anti-migratory drug candidates for clinical trials, identifying imipramine as a potential drug candidate. Based on preliminary data for the imipramine test group, “these cells initially have these long spiky protrusions that rapidly disappear.” Odde highlighted, “The cells kind of retract and were found to be non-migratory in the presence of imipramine.” In addition to his research, Odde also presented his plan for an imipramine clinical trial to treat glioblastoma. Audience members and other speakers provided feedback on the proposal.
Maximizing treatment efficacy
Symposium attendees also discussed improvements to existing glioblastoma treatments. Mayo Clinic Professor of Radiation Oncology Jann Sarkaria presented his latest work on radiosensitizers, which are vital in radiation treatment.
One of the most common treatment plans used for the treatment of glioblastoma is radiotherapy after a successful surgery removing the tumor. Radiation therapy uses high energy beams to damage DNA in the target cells and prevent cells from further growth. However, cancer cells retain the ability to fix breaks in their DNA just like normal cells, meaning that any damage done during radiation therapy could get repaired and remain ineffective.
Sarkaria’s research on radiosensitizers, specifically the ATM-kinase inhibitor, solves the potential flaw of radiation therapy. The ATM-kinase protein is one of the key proteins in the repair of DNA breaks. When activated, ATM-kinase controls cell checkpoints during growth and manages DNA repair operations. Sarkaria has tested his experiments in a PDX model, which is where a small piece of tissue from the patient is implanted into a humanized or immunodeficient mouse. The inhibitor was later tested in clinical trials.
For patients, radiation therapy is uncomfortable, to say the least, causing headaches, hair loss, seizures, nausea, and extreme fatigue. But according to Dr. Franziska Michor, Professor of Computational Biology at Harvard University, scientists might be able to use less radiation to get the same effect.
Like many other researchers in the field, Michor uses mice injected with glioblastomas to “characterize the microenvironment and the dynamics of radiation response of different subsets of cells.” In particular, she presented on “whether different radiation fractionation schedules might help maximize efficacy of a given amount of radiation.” The experiment, which involved two groups of mice injected with glioblastomas, was able to get the same survival rate for each group of mice, even though one was treated with twice as much radiation as the other.
In addition to creating an ideal radiation fractionation schedule, Michor conducted research on when to administer chemotherapy or immunotherapy drugs after radiation. Through a mathematical model of the treatment response, she estimated an ideal administration time of 41 minutes after radiation for mice, which scales up to 57 minutes after radiation for humans.
Through these scheduling methods, Michor hopes to reduce strain on the patient while maximizing damage to the tumor, ultimately improving survival. The schedules are now undergoing clinical trials.
Links to other cognitive functions
Some presenters also shared their research on the inner workings of glioblastoma and how it influences the rest of the brain. MIT Associate Professor of Biology Stefani Spranger discussed the interactions between two types of white blood cells, T lymphocytes and dendritic cells. Specifically, Spranger found that dendritic cells are vital in determining if the T lymphocytes in an immune response can mount an effective anti-tumor response or if they lead to an exhausted T lymphocyte response.
Stanford University Professor of Neurology and Neurological Sciences and a Howard Hughes Medical Institute Investigator Michelle Mongje presented her research on pediatric cases of glioblastoma tumors, and specifically, the interaction between the myelin sheath and tumors. The myelin sheath is one of the most important parts of a neuron; it wraps around the neuron like insulation on the outside of a wire, helping to accelerate the speed of a signal between neurons. The myelin sheath, however, is also linked to glioblastoma.
“When you take a step back and think about the developmental processes that might be correlated with the time and place incident of pediatric gliomas, it strikes you that developmental myelination is happening in the times and places tumors tend to form,” Monje said. A potential reason for this is the plasticity of myelin and the possibility of an oncogenic mutation — changes in myelin can improve connectivity in the brain, and any oncogenic mutation in the myelin can have a negative impact on the surrounding brain tissue.
Monje ended her presentation by stressing the fact that these qualities indicate that scientists must approach these cancers not just from the perspective of just tumors and cells, but also from a neuroscientific perspective as well.
Collaborating towards a cure
The Glioblastoma Systems Biology Glioblastoma Tumor Microenvironment Symposium is one of the events held by the MIT-DFCI Center for Glioblastoma Systems Biology, which was launched about a year and a half ago.
“I think you heard a lot of really exciting studies that are interconnected, and that’s kind of the beauty of this symposium and also the beauty of Forest [White]’s program,” Sarkaria reflected.
For White, the symposium is a chance for renewed optimism among glioblastoma researchers. “My hope is that by seeing the different approaches people are taking, they can try and sort of synergize some of those ideas to come up with new approaches,” he said. “From those new approaches, hopefully we can actually move treatment forward.”