Glioblastomas are the most common type of primary brain cancer in adults. As incurable tumors, they account for about half of all brain malignancies, according to the American Cancer Society. The 5-year survival rate is 9 percent for patients who are 45-54 years old and 6 percent for those ages 55-64. While younger patients fare better, overall survival is 8 months on average.
Glioblastomas are resistant to cancer treatments. The FDA has approved four drugs for brain tumors in the past 40 years, while the standard of care-surgery and concomitant and adjuvant chemotherapy-has remained unchanged since 2005. The treatments are considered harsh and potentially harmful not only to brain function but the entire human body.
In a recently published study, researchers at the Cleveland Clinic Lerner Research Institute in Ohio investigated the epigenetic process of glioblastoma and whether molecular mechanisms critical for cancer stem cells (CSCs) population maintenance may have any therapeutic potential. To find out, the cancer investigators created a screen to identify essential epigenetic regulators in glioblastoma in patient-derived organoids that were treated with a WDR5 inhibitor, which resulted in a dramatic loss of proliferating cells, including stem cells, and overall disease.
Detailing the results of the study in Genes & Development, the Cleveland Clinic researchers reported identifying WDR5 blocked proteins that promote positive regulation of transcription and expression of genes involved in CSC-relevant oncogenic pathways (2023; doi: 10.1101/gad.349803.122). Knocking down the epigenetic factor altered the stem cell state and disrupted CSC growth in vitro, said study author, Justin Lathia, PhD, a staff member in Cardiovascular & Metabolic Sciences and the Melvin H. Burkhardt Endowed Chair for Neuro-Oncology Clinical Research at Cleveland Clinic.
Two things stand out among many important new findings from the new study, Lathia told Oncology Times. "One is that we have a very clear role for this protein and also that glioblastoma is driving the cancer cell state. And the second thing is that we have proof of concept with the tool compound that you're actually inhibiting this [WDR5]," he said. "It gives us not only a basic biological understanding around the epigenetic factor WDR5 but, potentially, a translational opportunity. The tool compound doesn't effectively get to the brain, but that's what we're excited about."
Magnitude of Three
Something that surprised the researchers, Lathia said, was "the magnitude of change" observed in the study, "and how many genes and pathways, and networks in a cell change," he explained. "I think we underestimated the magnitude of change that occurred as the result of knocking down this pathway. We didn't expect hundreds of genes to change as a result of compromising this factor."
The new research follows a 2017 study in Cell Stem Cell by the Cleveland Clinic researchers. In that study, the cancer investigators discovered that toll-like receptor expression allows self-renewing CSCs to ignore hostile inflammatory signals inside tumors (https://doi.org/10.1016/j.stem.2016.12.001). "When we were doing that study, we actually found the pathway that is used to sense damage was suppressing an epigenetic factor called RB Binding Protein 5, which is part of a complex of other factors, and we wanted to understand better what each of these factors was doing," the researchers noted.
Toward that end, the Lathia Lab teamed up with two other labs at Cleveland Clinic, led by Shaun Stauffer, PhD, Director of the Center for Therapeutics Discovery, and Christopher Hubert, PhD, now Assistant Professor at Case Comprehensive Cancer Center at Case Western Reserve University. Kelly Mitchell, PhD, a recent postdoctoral fellow at Cleveland Clinic, was first author of the study.
The Hubert Lab "had done a large screen to understand what epigenetic factors were important. And their top hit was the protein we were interested in, which was WDR5," Lathia said.
Prior experience developing low molecular weight drugs, including inhibitors against the WDR5 protein, meanwhile, made researchers in the Stauffer Lab the ideal choice to help develop a tool compound capable of penetrating the blood-brain barrier.
"The three labs came together around the idea of, 'What is this WDR5 protein doing?' but also 'How do we target them?'" Lathia said. "So that's how we got here. Because we are really interested in understanding how certain tumor cells have an aberrant activation of developmental programs."
Development Potential
When it comes to the clinical implications of the study findings, Lathia pointed to the promising results realized so far.
"We are very interested in developing inhibitors that get into the brain, and we have had some very promising results with the tool compound," he said."Where we're at now is trying to develop brain-penetrating inhibitors."
The researchers have some pending IP structures and are hoping they will lead to structure-function studies in the near future. Further development might include licensing and even starting a company. Meanwhile, the Cleveland Clinic investigators will continue working on new therapeutics for patients with glioblastoma and potentially other cancers as well.
"Because we are at a hospital and we are very translational, the lion's share of our efforts right now is on academic drug development," Lathia said. "We're working with the medicinal chemistry team; they're making analogs, we're screening, those sorts of things."
Meanwhile, it is important to note that the epigenetic factor, WDR5, seems only to be found inside very aggressive glioblastoma tumor cells. "We don't think there is a lot of toxicity in other cells in the brain," Lathia said. "There's a therapeutic window I think we have an opportunity to exploit and that's what we are trying to do."
Chuck Holt is a contributing writer.
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