Innovations in Glioblastoma Research

Mina Lobbous, MD

Glioblastoma is among the most aggressive forms of brain cancer, presenting significant challenges to treatment and prognosis. Despite advancements in medical science, glioblastoma remains a formidable adversary with a median overall survival less than 2 years. Despite recent advances in multimodality treatment for glioblastoma incorporating surgery, radiotherapy, and systemic therapy, outcomes remain poor, necessitating more effective therapies built on better understanding of disease biology and mechanisms of treatment resistance.

In the United States, the average annual age-adjusted incidence of glioblastoma is 3.21 per 100,000 population, based on national registry data from 2011 through 2015. To this date, there are few validated risk factors for glioblastoma, with exposure to ionizing radiation being the only known potentially modifiable risk factor. Glioblastoma continues to have a poor prognosis. Advanced age, poor performance status, and incomplete extent of resection are all well-established negative prognostic factors. Despite years of clinical and basic research, it has been almost a decade since the last therapy for glioblastoma, Tumor Treating Fields, received FDA approval.

Glioblastoma drug discovery faces multifaceted challenges rooted in the complex nature of the disease and the unique characteristics of the brain. One of the foremost hurdles is the blood-brain barrier, which restricts the passage of many drugs into the brain, limiting their efficacy. Additionally, glioblastoma exhibits remarkable heterogeneity, with diverse molecular subtypes and genetic alterations among tumors and even within individual tumors. This heterogeneity complicates drug development efforts, as therapies must target a broad spectrum of tumor subtypes to be clinically impactful. Moreover, glioblastoma tumors often display intrinsic resistance to chemotherapy and radiation therapy, necessitating the identification of alternative treatment strategies to overcome resistance mechanisms. Furthermore, the lack of robust preclinical models that accurately recapitulate the complexity of glioblastoma hampers the translation of promising preclinical findings into clinical success. Addressing these challenges requires interdisciplinary collaboration, innovative research methodologies, and a comprehensive understanding of glioblastoma biology to drive the development of more effective therapeutic interventions.

To overcome such hurdles, researchers at Cleveland Clinic, for example, are studying disease biology and mechanisms to overcome tumor resistance to chemotherapy, through elucidating the tumor microenvironment, genetic alterations, and signaling pathways involved in glioblastoma pathogenesis, which enables the development of targeted therapies tailored to disrupt specific disease drivers. In a study led by Justin Lathia, PhD, researchers identified that T-cells become exhausted faster in men than in women with glioblastoma, a finding that will impact future personalized therapeutic development. In this study, which included preclinical models and patient samples, Lathia’s lab identified a new contributor to the differences in glioblastoma occurrence and prognosis between men and women. Checkpoint inhibitor therapies are designed to reverse T-cell exhaustion and bolster the body’s immune response. These data show that male and female T-cells are different – essentially operating on separate timelines – which suggests scientists need to develop separate treatment approaches. The Lathia Laboratory has studied the differences in glioblastoma between men and women for years, looking for insights that can help in providing better treatments for the disease. Previously, the group linked sex-based differences to myeloid cells in the bone marrow.

While the extent of surgical resection has been established as one of the prognostic factors in glioblastoma, prospective data on tailoring the resection and radiation targets are lacking. It is known that glioma cells and neurons communicate via electrical impulses and neurotransmitters, which subsequently lead to tumor cells migration and invasion. Jennifer Yu, MD, is leading a study with in-depth intraoperative recording of tumor electrical activity. Moreover, the study aims to determine the impact of high electrical activity and pattern of activity on tumor invasion, and mechanistic basis of its regulation and functional consequences. This phase I safety and feasibility study is being proposed as a first step toward dissecting the connection between electrical activity and glioma behavior. The goal is to determine the safety and feasibility of recording electrical activity in the tumor-neuron interface using technologies that are already being used clinically for participants undergoing brain surgery.

The window-of-opportunity surgery trial for glioblastoma presents a crucial avenue for accelerating drug development in this challenging disease. This innovative approach capitalizes on the unique opportunity provided by surgery to obtain tumor tissue samples before and after resection, enabling the study of tumor evolution and treatment response in real time. By analyzing these tissue samples using advanced molecular profiling techniques, researchers gain valuable insights into the dynamic changes occurring within the tumor microenvironment and the emergence of therapeutic resistance. Furthermore, this trial design allows for the rapid evaluation of novel therapeutic agents or drug combinations, facilitating the identification of promising candidates for further clinical development. Through close collaboration between surgeons, oncologists, and researchers, the window-of-opportunity surgery trial holds the potential to expedite the translation of basic science discoveries into clinically meaningful advancements in glioblastoma treatment.

Based on Cleveland Clinic Lerner Institute researchers’ preclinical models that identified hydrogen sulfide as a by-product that inhibits glioblastoma cell growth and migration, David Peereboom, MD, is leading a phase 1 surgical trial studying the safety and efficacy of methimazole, an antithyroid medication that is known to increase hydrogen sulfide production, along with chemotherapy in patients with progressive glioblastoma who are undergoing surgical resection.

Collaboration is key to accelerating progress in glioblastoma research, and Cleveland Clinic fosters partnerships with leading academic institutions, pharmaceutical companies, and patient advocacy groups. Through collaborative initiatives, researchers can leverage complementary expertise, share resources, and expedite the translation of scientific discoveries into clinical applications and the field of immuno-oncology has been at center stage of drug development at Cleveland Clinic. While immunotherapy has revolutionized cancer treatment, the results in glioblastoma to date remain suboptimal due to prior immunotherapy clinical trials design and lack of robust preclinical models. The team at Cleveland Clinic Center for Immunotherapy and Precision Immuno-Oncology, under the leadership of Timothy Chan, MD, PhD, brings together multidisciplinary experts to advance research and treatment related to the rapidly growing field of immuno-oncology through more personalized approaches that take into consideration the unique nature of glioblastoma. Through ongoing phase 2 clinical trials, the team at Cleveland Clinic Brain Tumor Center offers patients with glioblastoma novel immunotherapies including genetically modified gamma-delta T cells engineered to resist chemotherapies (DeltEx) under the direction of Dr. Lobbous, peptide immunotherapeutic vaccine (SurVaxM), and other immunomodulating therapies.

In the quest to conquer glioblastoma, the Cleveland Clinic stands at the vanguard of innovative research and discovery. Through precision medicine, immunotherapy advancements, blood-brain barrier breakthroughs, biomarker discovery, collaborative initiatives, and patient-centered care, researchers are driving progress toward more effective treatments and improved outcomes for glioblastoma patients. As we continue to unravel the complexities of this disease, hope shines ever brighter on the horizon, fueled by the dedication and ingenuity of the scientific community.