Every day oncologists enter an exam rooms to tell their patient that they have been diagnosed with glioblastoma (GBM) one of the most common, complex, treatment-resistant, and the deadliest types of brain cancer. The disease has a 5-year-survival rate of less than 10% and little progress has been made in battling brain cancer over the past 50 years.
Altough technically a rare disease, glioblastoma affects thousands of families each year. But being designated a rare disease, contributed to the fact that the disease receives little attention compared to other forms of cancer, such as breast cancer, lung cancer or pancreatic cancer, which are considered more prevalent cancers.
This changed bit when, in 2009, Senator Edward “Ted” Kennedy, a liberal Democrat and member of the United States Senate, died of the disease, and, less than a decade later, in late 2018, Kennedy was followed by another promenent member of Congress, Senator John McCain, a conservative Republican.
The unfortunate coincidence of two prominent members of Congress succumbing to glioblastgoma led the nonprofit ‘National Brain Tumor Society,’ reach out to group of bipartisan Senators to champion an effort to increase public awareness of the disease and set a day every year to remember the people lost and support patients, their caregivers and loved ones. Via a Senate resolution in 2019, and introduced through a Senate and House resolution in 2020, Glioblastoma Awareness Day (#GBMDay; July 22, 2020) was introduced as a day to raise the national consciousness about the disease as well as day of giving and action for glioblastoma research, treatments, and care.
Major unmet medical need
As a standard aproach to the treatment of glioblastoma, eligible patients disgnosed with the disease will have their tumor surgically resected. The purpose of this approach is to remove as much of the malignancy as possible while, at the same time, preserving neurological function.
Because glioblastoma is an infiltrative disease and, at the time of diagnosis, tumor cells may have spread from the primary lesion into the adjacent brain tissue, surgical resection is often followed by adjuvant radiation and temozolomide chemotherapy.
A new approach
Altough advantages have been made in the treatmemnt of glioblastoma, patients will eventually relapse. While these patients can be treated with reoperation and re-irradiation, these interventions have significant risks and are generally palliative rather than curative. As a result, there remains a significant unmet medical need, with a shortage of therapies that are both nontoxic and efficacious for patients with relapsed glioblastoma.
Among a potential treatment options being developed for the treatment of glioblastyoma is a new investigational drug called ONC201. This novel agent, being developped by Oncoceutics, is the first member of the imipridone class of small molecules. The compound, initially tested in patients with hematological malignancies and solid tumors, acts as a bitopic antagonist of the G protein-coupled receptor (GPCR), dopamine receptor D2 (DRD2), and an allosteric agonist of the mitochondrial protease caseinolytic protease P (ClpP).
Early preclinical development
In early preclinical development, ONC201, which, in mouse models, crosses the blood brain barrier and inhibits tumor growth, showed signs of efficacy against glioblastoma.
The investigational agent upregulates TRAIL, a member of the TNF superfamily that induces tumor-selective cell death, and induces apoptosis in several glioblastoma cell lines, including cell lines resistant to the standard of care temozolomide (Temodar®; Merck & Co/MSD). Furthermore, ONC201 also shows potent cytotoxicity in bevacizumab (Avastin®; Genetech/Roche), temozolomide, and radiation resistant glioblastoma patient samples.
ONC201, which is being studies in clinical trials, shows encouraging results for a subtype of brain cancer called H3 K27M-mutant glioma*. Study results with ONC201 in patients with glioblastoma in which this mutation occured were encouraging. Overall, ONC201 was well tolerated and may have single agent activity in recurrent glioblastoma patients.
In November 2018 the U.S. Food and Drug Administration (FDA) granted Fast Track designation to ONC201 for the treatment of adult recurrent H3 K27M-mutant high-grade glioma.
Isabel Arrillaga-Romany, MD, PhD. Associate Clinical Director, Neuro-Oncology, Massachusetts General Hospital Cancer Center, served as overall Principle Investigator (PI), site PI, and co-investigator, in several therapeutic and non-therapeutic clinical trials for patients with brain tumors including the Phase II trial of ONC201 in recurrent glioblastoma. Arrillaga-Romany recently spoke about the early results seen in that study, specifically the results seen in a patient with a tumor mutation (H3.3 K27M) which may confer particular sensitivity to ONC201.
Glioblastoma Awareness Day
“In commemorating [Glioblastoma Awareness Day], we recognize not only the patients currently battling GBM but also the families of those patients, the clinicians and caregivers treating them, the survivors, the patients who have lost their lives, and the researchers working to defeat this disease,” noted Lee Schalop, M.D., Chief Executive Officer of Oncoceutics.
“Over the last decades, little progress to secure new and effective treatments has been made in the battle against GBM, and there remains a strong need for new and innovative approaches to help change the future of this terrible disease,” Schalop added.
“Oncoceutics remains committed to changing the treatment landscape and drug development approach for brain cancer, and we are honored to work with leading cancer centers, researchers, and patient advocacy groups on that mission,” said Joshua Allen, PhD, Chief Scientific Officer of Oncoceutics.
“We strongly support [Glioblastoma Awareness Day] in bringing national attention to this terrible disease, and encourage the public to support patient advocacy groups, learn more about the latest treatment options, and join us in commemorating this day,” Allen concluded.
* Histone H3 K27M is a mutation in the H3F3A gene, encoding for histone H3.3.This mutation is characteristic of diffuse midline glioma, H3 K27M-mutant, a new entity in the classification of central nervous system tumors, which carries a poor prognosis. Diffuse midline glioma H3 K27M–mutant is a specific entity added to the 2016 update of the WHO classification of CNS tumors.
 Ralff MD, Lulla AR, Wagner J, El-Deiry WS. ONC201: a new treatment option being tested clinically for recurrent glioblastoma. Transl Cancer Res. 2017;6(Suppl 7):S1239-S1243. doi:10.21037/tcr.2017.10.03
 Arrillaga-Romany I, Chi AS, Allen JE, Oster W, Wen PY, Batchelor TT. A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Oncotarget. 2017;8(45):79298-79304. Published 2017 May 12. doi:10.18632/oncotarget.17837
Featured image: Despairing woman with brain cancer. Photo courtesy: © 2018 – 2020 Fotolia/Adobe. Used with permission.