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Brain Tumor Research Roundup – April 2019

Published on April 24, 2019 in Brain Tumor Information, Research, Clinical Trials

Over the years, NBTS has given nearly $40 million to brain tumor research projects. We’re very proud of the impact this funding has made in advancing the neuro-oncology field closer to better treatments and ultimately a cure. And while NBTS is currently focused on driving our flagship research projects – like the Defeat GBM (glioblastoma) Research Collaborative – forward, there also continues to be great scientific research efforts happening across the entire neuro-oncology field. This is critical, as no one researcher, one lab, or one institution can cure this disease alone. Below are highlights of some recently published research from the brain tumor scientific and medical community.

Results of a Phase Ib Trial of an Autologous Cell Vaccine for Newly Diagnosed Glioblastoma
Andrews DW, et al (2019) AACR Annual Meeting, CT038
> View the presentation abstract
> View the company press release

IGV-001 from Imvax is an experimental cancer-fighting vaccine made from patients’ own tumor cells that are removed at the time of surgery. IGV-001 was evaluated in small, early-phase (phase Ib) clinical trials for newly diagnosed glioblastoma patients. Interim data from that trial were recently reported at the American Association for Cancer Research (AACR) Annual Meeting in Atlanta.

The vaccine – which is made by treating the patient’s own tumor cells that are removed during surgery with an experimental anti-cancer drug and then loaded into bio-diffusion chambers the size of dimes that are placed in incisions made in the patient’s abdomen.  The vaccine works by training a patient’s immune system to recognize and fight their tumors. The bio-diffusion chambers are removed after 48 hours, and standard of care radiation and chemotherapy with temozolomide is administered 4-6 weeks later.

The data presented during the AACR conference showed preliminary signs that this treatment is capable of generating an effective immune response against glioblastoma tumors, with few significant negative side effects for patients.

Imvax will conduct additional clinical trials to ensure the early effects seen to date translate in larger studies in a greater number of patients. These later-phase trials will ultimately determine if IGV-001 is safe and effective and appropriate for FDA approval.

Modeling Patient-Derived Glioblastoma with Cerebral Organoids
Linkous, et al., Cell Reports (2019) 26, 3203-3211
> View the paper

Preclinical models are critical tools for scientists performing brain tumor research. These laboratory models are typically samples of tumor cells studied in petri dishes (in vitro models) or engrafted into mice to grow into tumors (in vivo models). However, traditional in vitro and in vivo model systems for researching brain tumors have a number of significant limitations that reduce the ability of researchers to predict and translate results from studies in laboratory models to actual patients. One major limitation of current brain tumor models is that, while some fairly accurately replicate the cancerous cells, they are unable to reliably capture the so-called “tumor microenvironment” which are the non-cancerous elements of a human organ that surround and interact with the tumor cells.

Researchers at NewYork-Presbyterian Hospital/Weil Cornell Medicine have now created a model system called “GLICO” (glioma cerebral organoids) – which have been described as 3D “mini-brains” – that more accurately mirrors both the tumor and its microenvironment of glioblastoma (GBM). The model is easy to tweak, which will allow researchers to continue to refine GLICO. Currently, the NewYork-Presbyterian Hospital/Weil Cornell Medicine team, led by Dr. Howard Fine, using novel bioengineering approaches to introduce elements that would mimic characteristics of the blood-brain barrier.

The GLICO model will serve as a “tool to study GBM biology in a human brain environment,” as well as for use in testing potential new drugs for glioblastoma patients.

Lomustine-Temozolomide Combination Therapy Versus Standard Temozolomide Therapy in Patients with Newly Diagnosed Glioblastoma with Methylated MGMT promoter – a Randomized, Open-Label, Phase III Trial (CeTeG/NOA-09)
Herrlinger U, et al., The Lancet (2019), 16;393(10172):678-688
> View the paper

A phase III clinical trial evaluated administering the chemotherapy drugs temozolomide and lomustine (CCNU) together with radiation in newly diagnosed glioblastoma patients versus patients receiving standard temozolomide and radiation. The trial, which took place across 17 different cancer centers and hospitals in Germany, included 129 patients (63 in the temozolomide only group and 66 in the lomustine-temozolomide group). There was no significant difference in these groups overall. However, when analyzing subpopulations, the researchers found that in patients with a genetic marker known as a “methylated MGMT promoter” median overall survival was improved from 31.4 months in the temozolomide-only group to 48.1 months in the lomustine-temozolomide group. The researchers say their results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. But they note that, at this time, their findings should be interpreted with caution, owing to the small size of the trial.

Target Identification Reveals Lanosterol Synthase as a Vulnerability in Glioma
Phillips R, et al., Proceedings of the National Academy of Sciences Apr 2019, 116 (16) 7957-7962
> View the paper

Researchers led by a team from Memorial Sloan Kettering Cancer Center (MSKCC) found that an experimental drug known as MI-2, known to work in leukemia, was effective at stopping tumor growth in mouse models of DIPG tumors. Through their experiments, the researchers found that MI-2 works by interrupting the tumor cells’ mechanism for maintaining increased cholesterol levels, killing the DIPG – but not healthy – cells. Specifically, they discovered that MI-2 blocks an enzyme in DIPG cells called “lanosterol synthase” that is involved in cholesterol production. This finding is consistent with previous research, funded by NBTS’s Defeat GBM Research Collaborative, showing that some brain cancer cells are particularly vulnerable to cholesterol depletion.

However, MI-2 might not be the most effective drug to target lanosterol synthase in DIPG patients because the compound is not optimized to target cancer in the brain. Therefore, researchers are hoping to develop compounds that are better suited to fight DIPG in human patients. They are also analyzing cholesterol reducing drugs that are already on the market.

“Some existing drugs, initially made for people with high cholesterol, were designed to target lanosterol synthase – but they were never really thought of as cancer drugs,” said Dr. Richard Phillips, a neuro-oncologist at MSKCC. “One of them is even more potent that MI-2, so we’re now working with a team of chemical biologists to see if we can modify the drug so it reaches the brain.”

Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma
Merchant T, et al., Journal of Clinical Oncology 2019 37:12, 974-983
> View the paper

The Children Oncology Group (COG) trial ACNS0121 recently published results from a phase II clinical trial for children with ependymoma. Data from the trial suggests that treating these patients with radiation immediately following surgery can significantly increase survival, potentially. COG is the world’s largest cooperative pediatric cancer research organization. ACNS0121 was the first cooperative group study to evaluate this approach in ependymoma patients under the age of three.

Ependymoma is the third most common form of pediatric brain tumor, and historically children under the age three have a worse prognosis than older pediatric patients. However, results from this trial found that even young children with ependymoma benefited from radiation given immediately after surgery. Post-operative radiation was demonstrated to help achieve seven-year progression-free survival for more than 75% of patients, and overall survival for 85% of patients, despite age.

“These results are already shifting the standard of care for patients with ependymoma because the clinical trial used standard conformal radiation, which is widely available,” said Dr. Maryam, Fouladi, chair of the COG Central Nervous System Committee.

The trial was available at more than 100 cancer centers and hospital and enrolled nearly 400 patients. Participants ranged in age from 1-21 years old and were followed-up after treatment to evaluate any potential long-term impacts of the therapy.

Myc and Loss of p53 Cooperate to Drive Formation of Choroid Plexus Carcinoma
Wang J, et al., Cancer Res March 18 2019, DOI: 10.1158/0008-5472.CAN-18-2565
> View the paper

Choroid plexus carcinoma (CPC) is a particularly challenging type of pediatric brain cancer, most commonly arising in infants under the age of one—who are too young to undergo radiation treatment. As such, only 40% of children remain alive five years after diagnosis. Progress in developing effective therapies has been hindered by the lack of models that could help researchers better understand the cancer.

Now, scientists from Sanford Burnham Prebys Medical Discovery Institute at San Diego, CA have developed a novel mouse model of CPC through genetic engineering methods. Tumors isolated from these mice mirrored the human cancer and the models have been used to identify potential drugs that may be effective for CPC patients.

“This model is a valuable tool that will increase our understanding of the biology of the cancer and allow us to identify and test novel approaches to therapy,” said Robert Wechsler-Reya, Ph.D., senior author of the paper, professor and director of the Tumor Initiation and Maintenance Program at Sanford Burnham Prebys, and program director of the Joseph Clayes III Research Center for Neuro-Oncology and Genomics at the Rady Children’s Institute for Genomic Medicine.

The newly available model allowed the scientists to test compounds that could stop or slow the growth of the tumor. The researchers conducted a high-throughput screen of nearly 8,000 compounds against the mouse tumor cells. The screen revealed three compounds that reduced the growth of the cancer cells, without harming healthy brain cells – investigational drugs dinaciclib and flavopiridol, and a natural product, triptolide.

“These compounds are promising, much-needed leads in the quest for an effective CPC treatment,” said Dr. Wechsler-Reya. “Our laboratory plans to evaluate these and additional compounds that can effectively treat this cancer.”

This research was funded in part through a grant to Dr. Wechsler-Reya from the National Brain Tumor Society’s past pediatric research program, the Developmental Neurobiology Initiative.

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