Advances in Glioblastoma Research

Rostomily and his team are focused on improving the effectiveness of the standard GBM therapies. By using knockdown models along with complementing in vivo and in vitro studies, Rostomily identified novel agents that can be used to treat GBMs. Specifically, bis-indole-derived dual NR4A1/2 (Nuclear Receptor Subfamily 4) inverse agonists were demonstrated to regulate the expression of TWIST1 – a pro-oncogenic factor regulating EMT in GBMs.

TWIST1 is a master regulator of EMT and its role in GBMs was first reported by Rostomily, who has shed light on the mechanism of regulation of TWIST1. For example, Rostomily and his colleagues research scientist Andrei Mikheev, MD, PhD at Houston Methodist Research Institute and Steve Safe, PhD at Texas A&M University, demonstrated for the first time that NR4A1 and NR4A2 are upstream regulators of TWIST1 expression. Loss-of-function studies indicated the therapeutic potential of inhibiting TWIST1 and/or its related pathways and regulated targets.

Since transcription factors driving EMT cannot be directly targeted, they targeted the upstream "druggable" kinases whose inhibition demonstrated effectiveness in the preclinical studies in combination with the standard-of-care treatment. “The lack of current treatment efficacy for GBM has spurred a significant amount of research on the development of alternative therapies, including agents/biotherapeutics that target receptor tyrosine kinases, angiogenesis pathways, and other factors. Presently, these therapies are not routinely used for clinical treatment of GBM either because of lack of efficacy or challenges posed by intra-tumoral cellular and molecular heterogeneity,” commented Rostomily. “Along with our colleagues at Texas A&M, we recently demonstrated that a series of highly potent agents inhibited tumor growth in vivo and subsequently demonstrated that these compounds were dual NR4A1/2 ligands,” Rostomily added.

The immune system eliminates tumors through the cancer-immune cycle. However, in some cases, tumors evade immune surveillance by manipulating the TIME. The outcome depends on the balance of pro-tumor and anti-tumor activities within the TIME. While immunotherapy restores the tumor-killing ability of anti-tumor immune cells, the tumors attempt to create an immunosuppressive microenvironment. The team is also testing innovative combination drug regimens in preclinical settings, which includes testing and repurposing Food and Drug Administration (FDA)- approved drugs. Combination anti-tumor therapy is becoming increasingly useful owing to the resistant nature of GBMs, and the inability of anti-glioma drugs to cross the blood-brain barrier. According to Rostomily, “Combination therapy and drug synergism for targeted heterogeneous tumors and the interacting tumor microenvironment holds promise. Future research should focus on identifying synergistic interactions between chemotherapy, radiotherapy and immunotherapy in order to maximize the antitumor potential of individual treatment approaches.” He is also investigating how to leverage the electrophysiology of brain cancer and brain cancer stem cells. Cancer stem cells (CSCs) play crucial roles in the development and progression of GBM and brain metastases. By understanding novel mechanisms that regulate the phenotype of the CSCs, Rostomily hopes to identify and develop potential therapeutic targets and brain theranostics.

In collaboration with researchers at Baylor College of Medicine and Texas A&M , Rostomily’s team is developing high-throughput platforms to identify candidate drugs that can modulate the electrophysiologic properties of glioblastoma CSCs to achieve more treatment-responsive states. Specifically, they are using optogenetic regulation of the voltage potential across the cell membrane and multiplexed high-throughput screens with genetically engineered voltage indicators and cell cycle reporters to identify potential ion channel drugs that can be repurposed to enhance GBM or metastatic CSC response to therapy. “Repurposing ion channel drugs and having new delivery systems could fundamentally change the way the tumors behave,” Rostomily noted. He also believes coding technologies could be married together to leverage the electrophysiology component of the brain tumor. Additional areas of research include brain metastasis biology, aging and glioma malignancy, and studying the impact of pre-analytical variables on the accurate assessment of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, a crucial biomarker in GBMs. The Rostomily Lab also oversees the Neural Biorepository Core, which oversees comprehensive retrospective and prospective clinical databases related to brain, spinal metastases and gliomas. This Core collects about 100 patient-derived samples annually and provides these samples to facilitate collaborative basic and translational research across the Texas Medical Center on topics related to neuroscience. Rostomily, who has a long-standing interest in neuro-oncology, commented, “A significant amount of chemotherapy drugs are constantly being released. So, the important question is, how do we avoid complications from chemotherapy and from radiotherapy? How do we do a better job of predicting what the right treatment is for an individual patient? And how do you combine the drugs and radiation therapy rationally to treat an individual patient? There are too many variables to answer these questions with the standard clinical trial approach. Tackling these complex challenges and making a significant impact requires a massive amount of data. I believe if we can develop pipelines, templates to apply artificial intelligence, create our internal systems and recruit additional institutions to form a consortium, we may move closer to more robust and impactful insights.”